KR20140039161A - Isoxazolidine derivatives - Google Patents

Abstract

The present invention relates to novel anti-inflammatory and anti-allergic compounds of the glucocorticosteroid family, methods of preparing such compounds, pharmaceutical compositions comprising them, combinations thereof and therapeutic uses. More specifically, the present invention relates to glucocorticosteroids which are derivatives of isooxazolidine.

Description

Ixoxazolidine derivatives {ISOXAZOLIDINE DERIVATIVES}

The present invention relates to novel anti-inflammatory compounds and anti-allergic compounds of the glucocorticosteroid family, methods for preparing such compounds, pharmaceutical compositions comprising them, combinations thereof and therapeutic uses. More specifically, the present invention relates to glucocorticosteroids which are isooxazolidine derivatives.

Corticosteroids are potent anti-inflammatory agents that can reduce the number, activity and migration of inflammatory cells.

They are commonly used to treat a wide range of chronic and acute inflammatory diseases including asthma, chronic obstructive pulmonary disease (COPD), allergic rhinitis, rheumatoid arthritis, inflammatory bowel disease and autoimmune diseases.

Corticosteroids mediate effects through the glucocorticoid receptor (GR). The binding of corticosteroids to GR induces their migration into the nucleus, which leads to DNA-binding-dependent (eg, transactivation) and DNA-binding-independent (eg, trans expression) mechanisms. Through multiple downstream pathways.

Corticosteroids for the treatment of chronic inflammatory diseases in the lungs such as asthma and COPD are currently being administered via inhalation. The advantage of using inhaled corticosteroids (ICS) is that the drug can be delivered directly to the site of action, systemic side effects can be minimized, resulting in a faster clinical response and higher treatment rates. Is the point.

Although ICS treatment can bring significant benefits, especially in asthma, it is important to minimize ICS systemic exposure, which leads to the occurrence and severity of unwanted side effects that may be associated with chronic administration. Moreover, the availability of ICS for a limited period of time in clinical practice makes it less than optimal for the management of the disease. Although inhalation technology is a key factor for reaching the lungs, regulation of substituents on the corticosteroid molecular scaffolds reduces oral bioavailability, limits pharmacological activity in the lungs (prodrugs and soft drugs), and systemic In order to increase the clearance rate, it is important to optimize the pharmacokinetic and pharmacodynamic properties. Moreover, administration of ICS once a day can lower the frequency of administration, thereby substantially improving patient comfort and, consequently, improving the management and control of the disease, thus improving the long-term maintenance of ICS in the lungs. Activity is very desirable. Taken together, the need for developing ICS with improved pharmacokinetic and pharmacological properties continues in the medical community.

See, eg, WO 2006/005611, GB 1578446 and “Synthesis and topical antiinflammatory activity of some steroidal [16α, 17α-d] isoxazolidines” (J. Med. Chem., 25, 1492-1495, 1982). Dean derivatives are disclosed.

Co-pending application WO 2011/029547 also discloses some glucocorticoid isoxazolidine derivatives.

Surprisingly, the compounds of the present invention have been found to exhibit improved development, pharmacokinetic and pharmacologic properties such as low systemic exposure, high selectivity, efficacy or duration of action.

SUMMARY OF THE INVENTION

Accordingly, the present invention relates to glucocorticosteroid-based anti-inflammatory compounds and antiallergic compounds, processes for their preparation, compositions comprising them, therapeutic uses thereof and other pharmacologically active ingredients for treating respiratory diseases (beta 2 -agonists, (P38 MAP kinase) inhibitor, a nuclear factor kappa-B kinase subunit beta (IKK2) inhibitor, a human neutrophil elastase (HNE) inhibitor, a phosphodiesterase 4 (P38 MAP kinase) inhibitor, PDE4) inhibitors, leukotriene modulators, nonsteroidal anti-inflammatory agents (NSAIDs) and mucomodulators).

In particular, the present invention relates to compounds of formula (I) and pharmaceutically acceptable salts thereof.

[Formula (I)]

Wherein,

And _{(CH 2) n -Z- (CH} 2) n '-R 4, - - R 1 is

n is 0, 1 or 2;

n ' is 0, 1 or 2;

Z is a single bond or is selected from the group consisting of -S-, -O-, -C (O)-and -NR _3- ;

R ₃ is H, (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) haloalkyl, (C ₃ -C ₈ ) cycloalkyl, aryl, aryl (C ₁ -C ₆ ) alkyl and heteroaryl ( They are optionally substituted with -CN);

-R ₄ is

-H, halogen, -OH, -SH, -CN and -NR ₆ R ₇ ;

-Aryl (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkylsulfonyl, (C ₁ -C ₆ ) alkylcarbonyl, (C ₁ -C ₆ ) alkylcarboxyl, HO (C ₁ -C ₆ ) alkylcarboxyl, (C ₁ -C ₆ ) alkylamide and (C ₁ -C ₆ ) alkoxy, which are optionally substituted with oxo groups;

(C ₁ -C ₆ ) alkyl optionally substituted by one or more substituents selected from the group consisting of -halogen atom, -CN, -OH, -NH ₂ , -NO ₂ , -CF ₃ and -SH;

-(C ₂ -C ₆ ) alkynyl;

-(C ₅ -C ₁₇ ) alkenylcarbonyl; And

-Mono-, non- or tricyclic saturated or partially saturated or unsaturated rings (eg, (C ₃ -C ₈ ) cycloalkyl, aryl, (C ₅ -C ₁₀ ) heterocycloalkyl or heteroaryl), [ Wherein they are optionally substituted with one or more halogen atoms or oxo groups]

It is selected from the group consisting of;

R ₆ and R ₇ are independently selected from the group consisting of H, (C ₁ -C ₆ ) alkyl and (C ₁ -C ₆ ) alkoxy;

X and Y are independently H or a halogen atom;

R ₂ is-(CH ₂ ) _s -KA- (CH ₂ ) _t -W,-(CH ₂ ) _s -K- (CH ₂ ) _t -BW, and-(CH ₂ ) _S- (CHR ₅ ) -W is selected from the group consisting of;

s is 0 or 1;

t is 0 or 1;

-K is —CH═CH—groups, arylene groups and heteroarylene groups (such arylene and heteroarylene groups are halogen, (C ₁ -C ₆ ) alkyl, -OH, (C ₁ -C ₆ ) alkoxy and (C ₁ -C ₆ ) optionally substituted with one or more groups independently selected from haloalkyl);

A is selected from the group consisting of a single bond, an -O- group and an -S- group;

B is selected from the group consisting of a single bond, an -O- group and an -S- group;

-W is aryl or heteroaryl, which aryl and heteroaryl groups are independently from halogen, -OH, (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy and (C ₁ -C ₆ ) haloalkyl Optionally substituted by one or more groups selected;

R ₅ is aryl or heteroaryl, which aryl and heteroaryl groups are independent from halogen, (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy, -OH and (C ₁ -C ₆ ) haloalkyl May be optionally substituted by one or more groups selected from

However, in the compound of formula (I), when s is 1, K is optionally substituted heteroarylene, t is 0, A or B is a single bond, W is optionally substituted heteroaryl do.

In one embodiment, there is provided a compound of Formula (IA) and a pharmaceutically acceptable salt thereof.

[Formula (IA)]

Wherein,

And _{(CH 2) n -Z- (CH} 2) n '-R 4, - - R 1 is

n is 0, 1 or 2;

n ' is 0, 1 or 2;

Z is a single bond or is selected from the group consisting of -S-, -O-, -C (O)-and -NR _3- ;

R ₃ is H, (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) haloalkyl, (C ₃ -C ₈ ) cycloalkyl, aryl, aryl (C ₁ -C ₆ ) alkyl and heteroaryl ( They are optionally substituted with -CN);

-R ₄ is

-H, halogen, -OH, -SH, -CN and -NR ₆ R ₇ ;

-Aryl (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkylsulfonyl, (C ₁ -C ₆ ) alkylcarbonyl, (C ₁ -C ₆ ) alkylcarboxyl, HO (C ₁ -C ₆ ) alkylcarboxyl, (C ₁ -C ₆ ) alkylamide and (C ₁ -C ₆ ) alkoxy, which are optionally substituted with oxo groups;

(C ₁ -C ₆ ) alkyl optionally substituted by one or more substituents selected from the group consisting of -halogen atom, -CN, -OH, -NH ₂ , -NO ₂ , -CF ₃ and -SH;

-(C ₂ -C ₆ ) alkynyl;

-(C ₅ -C ₁₇ ) alkenylcarbonyl; And

-Mono-, non- or tricyclic saturated or partially saturated or unsaturated rings (eg, (C ₃ -C ₈ ) cycloalkyl, aryl, (C ₅ -C ₁₀ ) heterocycloalkyl or heteroaryl), [ Wherein they are optionally substituted with one or more halogen atoms or oxo groups]

It is selected from the group consisting of;

R ₆ and R ₇ are independently selected from the group consisting of H, (C ₁ -C ₆ ) alkyl and (C ₁ -C ₆ ) alkoxy;

X and Y are independently H or a halogen atom;

R ₂ is-(CH ₂ ) _s -KA- (CH ₂ ) _t -W,-(CH ₂ ) _s -K- (CH ₂ ) _t -BW, and-(CH ₂ ) _S- (CHR ₅ ) -W is selected from the group consisting of;

s is 0 or 1;

t is 0 or 1;

-K is —CH═CH—groups, arylene groups and hetero arylene groups (such arylene and heteroarylene groups are halogen, (C ₁ -C ₆ ) alkyl, -OH, (C ₁ -C ₆ ) alkoxy and (C ₁ -C ₆ ) optionally substituted with one or more groups independently selected from haloalkyl);

A is selected from the group consisting of a single bond, an -O- group and an -S- group;

B is selected from the group consisting of a single bond, an -O- group and an -S- group;

-W is aryl or heteroaryl, which aryl and heteroaryl groups are independently from halogen, -OH, (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy and (C ₁ -C ₆ ) haloalkyl Optionally substituted by one or more groups selected;

R ₅ is aryl or heteroaryl, which aryl and heteroaryl groups are independent from halogen, (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy, -OH and (C ₁ -C ₆ ) haloalkyl May be optionally substituted by one or more groups selected from

Except that the compounds of formula (IA) are:

(4aS, 4bR, 5S, 6aS, 6bR, 9aS, 10aS, 10bS, 12S) -4b, 12-difluoro-5-hydroxy-6b- (2-hydroxy-acetyl) -4a, 6a-dimethyl- 8- (2-phenyl-thiazol-4-ylmethyl) -4a, 4b, 5,6,6a, 6b, 8,9,9a, 10,10a, 10b, 11,12-tetradecahydro-7- Oxa-8-aza-pentaleno [2,1-a] phenanthren-2-one;

(4aS, 4bR, 5S, 6aS, 6bR, 9aS, 10aS, 10bS, 1S) -4b, 12-difluoro-5-hydroxy-6b- (2-hydroxy-acetyl) -4a, 6a-dimethyl- 8- (5-phenyl-furan-2-ylmethyl) -4a, 4b, 5,6,6a, 6b, 8,9,9a, 10,10a, 10b, 11,12-tetradecahydro-7-oxa -8-aza-pentaleno [2,1-a] phenanthren-2-one;

(4aS, 4bR, 5S, 6aS, 6bR, 9aS, 10aS, 10bs, 12S) -4b, 12-difluoro-5-hydroxy-6b- (2-hydroxy-acetyl) -4a, 6a-dimethyl- 8- (5-phenyl-isoxazol-3-ylmethyl) -4a, 4b, 5,6,6a, 6b, 8,9,9a, 10,10a, 10b, 11,12-tetradecahydro-7 Oxa-8-aza-pentaleno [2,1-a] phenanthren-2-one.

In this specification, unless stated otherwise, the term "halogen" includes fluorine, chlorine, bromine and iodine atoms.

The term "(C ₁ -C ₆ ) alkyl" refers to straight or branched chain alkyl having 1 to 6 carbon atoms. Examples of such functional groups are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl and the like.

The expression "(C ₁ -C ₆ ) alkylcarboxyl" refers to an alkyl-COO group.

The expression "(C ₁ -C ₆ ) alkylcarbonyl" refers to the group-(C ₁ -C ₆ ) alkyl CO-.

The expression "(C ₁ -C ₆ ) alkylamide" refers to a -C (O) -NH- (C ₁ -C ₆ ) alkyl group.

The expression “(C ₅ -C ₁₇ ) alkenyl” refers to a straight or branched chain, conjugated or in the range of 5 to 17 atoms having one or more double bonds in a cis or trans configuration. It refers to a non-conjugated carbon chain.

Examples of such functional groups are trans octadec-9-enyl, cis 9-octadec-9-enyl, cis, cis-9,12-octadecadienyl and hexadec-9-enyl.

The expression "(C ₅ -C ₁₇ ) alkenylcarbonyl" refers to a (C ₅ -C ₁₇ ) alkenyl -CO- group.

"(C ₂ -C ₆ ) alkynyl" refers to a straight or branched carbon chain in the range of 2 to 6 atoms having one or more triple bonds.

“(C ₁ -C ₆ ) alkoxy” refers to an alkyl-oxy (eg alkoxy) group as described above. Examples of such groups are methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentoxy, hexoxy and the like.

The expressions "(C ₁ -C ₆ ) alkoxycarbonyl" and "hydroxy (C ₁ -C ₆ ) alkoxy" refer to alkoxy-CO- and (OH) alkoxy- groups, respectively.

The expressions "(C ₁ -C ₆ ) haloalkyl" and "(C ₁ -C ₆ ) haloalkoxy" refer to the aforementioned "(C ₁ -C ₆ ) alkyl" and "(C ₁ -C ₆ ) alkoxy" groups In this case, one or more hydrogen atoms are substituted with one or more halogen atoms, which may be the same or different from each other.

Examples of such "(C ₁ -C ₆ ) haloalkyl" groups and "(C ₁ -C ₆ ) haloalkoxy" groups are halogenated, poly-halogenated and fully halogenated alkyl and alkoxy groups, both of which hydrogen atoms Is substituted with a halogen atom, such as a trifluoromethyl or trifluoromethoxyl group.

The expression "(C ₃ -C ₈ ) cycloalkyl" refers to a mono or bicycloaliphatic hydrocarbon group having 3 to 8 carbon atoms. Examples are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like.

The expression "(C ₅ -C ₁₀₎ heterocycloalkyl" is at least one ring carbon atom is a hetero atom or a hetero aromatic group which is substituted with a (e. G., N, NH, S or O) (C ₅ -C ₁₀₎ cycloalkyl Refers to an alkyl group.

The term "aryl" refers to monocyclic, or bicyclic or tricyclic, having 6 to 20 ring atoms, preferably 6 to 15 ring atoms, wherein at least one ring is aromatic.

The expressions "aryloxy" and "arylthio" refer to the aryl-oxy and aryl-S- groups as described above, respectively.

The term "aryl (C ₁ -C ₆ ) alkyl" refers to a "(C ₁ -C ₆ ) alkyl" group as described above in which one hydrogen atom is substituted with an "aryl" group as described above. An example is a benzyl group.

The expression “(C ₁ -C ₆ ) alkylsulfonyl” refers to an alkyl-SO ₂ group.

The expression “heteroaryl” refers to a monocyclic, bicyclic or tricyclic ring system having 5 to 20 ring atoms, preferably 5 to 15 ring atoms, wherein at least one ring is aromatic, One or more carbon ring atoms refers to a ring system that is a hetero atom or a heteroaromatic group (eg, N, NH, S or O).

Examples of suitable aryl or heteroaryl monocyclic systems include, for example, thiophene, benzene, pyrrole, pyrazole, imidazole, isoxazole, oxazole, isothiazole, thiazole, pyridine, imidazolidine, furan radical Etc.

Examples of suitable aryl or heteroaryl bicyclic systems include naphthalene, biphenylene, purine, putridine, benzotriazole, quinoline, isoquinoline, indole, isoindole, benzothiophene, dihydrobenzo dioxin, dihydro Benzo dioxepin, dihydrobenzo oxazine radical, and the like.

Examples of suitable aryl or heteroaryl tricyclic systems are the benzocondensation derivatives of the aforementioned heteroaryl bicyclic systems, including fluorene radicals.

By analogy, the expressions “arylene” and “heteroarylene” refer to divalent aryl (eg, phenylene) or heteroaryl radicals, where the aryl and heteroaryl groups are as described above.

It will be apparent to those skilled in the art that the compound of formula (I) has an asymmetric center at least at positions 4a, 4b, 5, 6a, 6b, 9a, 10a, 10b and can therefore exist as its various optical isomers and mixtures thereof. Do.

Thus, the invention also relates to all such isomers and mixtures.

Preferred compounds are those of formula (I), wherein the stereochemistry of the stereogenic carbon atoms is as described in formula (I ') below, where R ₁ and R ₂ , X and Y are of formula (I) Refers to a compound as defined above for the compound.

Formula (I ')]

Also preferred are compounds of formula (IA), wherein the stereochemistry of the stereogenic carbon atoms is as described in formula (IA ') below, and R ₁ and R ₂ , X and Y are relative to the compound of formula (IA). Compound of formula (IA) as defined above.

[Formula (IA ')]

Absolute configuration is assigned based on the Cahn-Ingold-Prelog nomenclature according to the priority of the functional groups.

In a preferred embodiment, in the compound of formula (I ') or (IA'), the complete structure of the asymmetric center 4a is (S), (R) at 4b, (S) at 5, (S) at 6a (S ), 6b to (R), 9a to (S), 10a to (S), 10b to (S), and 12 to (S).

Compounds of formula (I) or (IA) may form acid addition salts or base addition salts, in particular pharmaceutically acceptable salts.

Pharmaceutically acceptable acid addition salts of compounds of formula (I) or (IA) and therefore of compounds comprising formula (I ') or (IA') include, for example, hydrofluoric acid, chloric acid, bromic acid or iodic acid. Hydrogenated halogenic acids such as; Inorganic acids such as nitric acid, sulfuric acid and phosphoric acid; Examples thereof include aliphatic monocarboxylic acids such as formic acid, acetic acid, trifluoroacetic acid and propionic acid; aliphatic carboxylic acids such as lactic acid, citric acid, tartaric acid or malic acid; and dicarboxylic acids such as maleic acid, fumaric acid, oxalic acid or succinic acid, Aromatic carboxylic acids such as and the like, and organic acids such as aromatic hydroxyl acids and sulfonic acids.

A pharmaceutically acceptable base addition salt is one of formula (I), which is suitably modified by converting the parent compound, if present, into a corresponding addition salt using a suitable pharmaceutically acceptable base, or Derivatives of the compounds of (IA).

Examples of suitable salts may be mineral or organic salt addition salts of acid residues such as carboxyl groups.

The cations of the inorganic salts that can be suitably used to prepare the salts included in the present invention include ions of alkali or alkaline earth metals such as potassium, sodium, calcium or magnesium.

From the compounds of the formula (I), (I '), (IA) or (IA'), the salts can be prepared using well known salt formation methods.

All preferred functional groups or embodiments described below for compounds of formula (I) can be combined with each other and also formulas (IA), (I '), (IA'), (IB), (IC), (ID) It will be appreciated that the compound may be applied to a slight modification of a compound such as), (IE), (IF), or the above formula.

In a preferred embodiment, at least one of X and Y in the compound of formula (I) is a halogen atom. In a further preferred embodiment, both X and Y are halogen atoms. In even more preferred embodiments, X and Y are fluorine.

In a preferred embodiment, in the compound of formula (I), R ₁ is _{- (CH 2) n -Z- (} CH 2) n '-R 4 ( wherein, n is 1, Z is a single bond, n' is 0, R ₄ is or an -OH group), R ₁ is _{- (CH 2) n -Z- (} CH 2) n '-R 4 Where n is 0, Z is -S-, n 'is 1 and R ₄ is a halogen atom, or R ₁ is-(CH ₂ ) _n -Z- (CH ₂ ) _n' -R ₄ ( Where n is 0, Z is a single bond, n 'is 1, and R ₄ is a halogen atom. In a more preferred embodiment, R ₁ is _{- (CH 2) n -Z- (} CH 2) n '-R 4 Where n is 0, Z is -S-, n 'is 1 and R ₄ is a halogen atom, or R ₁ is-(CH ₂ ) _n -Z- (CH ₂ ) _n' -R ₄ ( N is 0, Z is a single bond, n 'is 1, and R ₄ is a halogen atom. In an even more preferred embodiment, R ₁ is-(CH ₂ ) _n -Z- (CH ₂ ) _{n '} -R ₄ , where n is 0, Z is -S-, n' is 1, and R ₄ is or a halogen atom), or R ₁ is _{- (CH 2) n -Z- (} CH 2) n '-R 4 Wherein n is 1, Z is a single bond, n 'is 0, and R ₄ is an -OH group.

A preferably is, R ₁ is _{- (CH 2) n -Z- (} CH 2) n '-R 4 (Wherein n is 1, Z is a single bond, n 'is 0 and R ₄ is an -OH group).

In another embodiment, R ₁ is — (CH ₂ ) _n -Z- (CH ₂ ) _{n '} -R ₄ (Where n is 0, Z is -S-, n 'is 1 and R ₄ is a halogen atom). Preferably the halogen atom is fluorine.

In another embodiment, R ₁ is — (CH ₂ ) _n -Z- (CH ₂ ) _{n '} -R ₄ (Wherein n is 0, Z is a single bond, n 'is 1 and R ₄ is a halogen atom). Preferably the halogen atom is fluorine.

In a preferred embodiment, R ₂ is a — (CH ₂ ) _S — (CHR ₅ ) —W group.

In a further preferred embodiment, R ₂ is a-(CH ₂ ) _s -KA- (CH ₂ ) _t -W group or a-(CH ₂ ) _s -K- (CH ₂ ) _t -BW group.

In a preferred embodiment, in the compound of formula (I), s is zero.

In another preferred embodiment, in the compound of formula (I), s is 1.

In a preferred embodiment, K is a -CH = CH- group. In a more preferred embodiment, K is optionally substituted arylene and heteroarylene.

In a preferred embodiment, in compounds of formula (I), R ₂ is _{- (CH 2) s -KA- (} CH 2) t -W or _{- (CH 2) S -K- (} CH 2) t -BW Selected from the group consisting of s being 0 or 1; K is optionally substituted arylene or heteroarylene; A is selected from the group consisting of a single bond, an -O- group and an -S- group; B is selected from the group consisting of a single bond, an -O- group and an -S- group; t is 0 or 1; W is optionally substituted aryl or heteroaryl.

In another preferred embodiment, in compounds of formula (I), R ₂ is _{- (CH 2) s -KA- (} CH 2) t -W or _{- (CH 2) S -K- (} CH 2) t - BW, wherein s is 0 or 1; K is optionally substituted arylene or heteroarylene; A is selected from the group consisting of a single bond, an -O- group and an -S- group; B is selected from the group consisting of a single bond, an -O- group and an -S- group; t is 1; W is optionally substituted aryl or heteroaryl.

In another embodiment, in compounds of formula (I), R ₂ is _{- (CH 2) s -KA- (} CH 2) t -W or _{- (CH 2) S -K- (} CH 2) t -BW Selected from the group consisting of s being 0 or 1; K is optionally substituted arylene; A is selected from the group consisting of a single bond, an -O- group and an -S- group; B is selected from the group consisting of a single bond, an -O- group and an -S- group; t is 0 or 1; W is optionally substituted aryl or heteroaryl.

In another embodiment, R ₂ is selected from the group consisting of-(CH ₂ ) _s -KA- (CH ₂ ) _t -W or-(CH ₂ ) _S -K- (CH ₂ ) _t -BW, wherein s is 0; K is optionally substituted arylene or heteroarylene; A is selected from the group consisting of a single bond, an -O- group and an -S- group; B is selected from the group consisting of a single bond, an -O- group and an -S- group; t is 0 or 1; W is optionally substituted aryl or heteroaryl.

In another embodiment, R ₂ is selected from the group consisting of-(CH ₂ ) _s -KA- (CH ₂ ) _t -W or-(CH ₂ ) _S -K- (CH ₂ ) _t -BW, wherein s is 1; K is optionally substituted arylene or heteroarylene; A is selected from the group consisting of a single bond, an -O- group and an -S- group; B is selected from the group consisting of a single bond, an -O- group and an -S- group; t is 0 or 1; W is optionally substituted aryl or heteroaryl.

In another embodiment, R ₂ is selected from the group consisting of-(CH ₂ ) _s -KA- (CH ₂ ) _t -W or-(CH ₂ ) _S -K- (CH ₂ ) _t -BW, wherein s is 1; K is optionally substituted arylene; A is selected from the group consisting of a single bond, an -O- group and an -S- group; B is selected from the group consisting of a single bond, an -O- group and an -S- group; t is 0 or 1; W is optionally substituted aryl.

In another preferred embodiment, R ₂ is selected from the group consisting of-(CH ₂ ) _s -KA- (CH ₂ ) _t -W or-(CH ₂ ) _S -K- (CH ₂ ) _t -BW, Where s is 1; K is optionally substituted arylene; A is selected from the group consisting of a single bond, an -O- group and an -S- group; B is selected from the group consisting of a single bond, an -O- group and an -S- group; t is 0 or 1; W is optionally substituted heteroaryl.

In a preferred embodiment, s is 0 or 1; K is optionally substituted arylene or heteroarylene; A is an -O- group; t is 0 or 1; W is optionally substituted aryl or heteroaryl.

In another preferred embodiment s is 0 or 1; K is optionally substituted arylene or heteroarylene; B is an -O- group; t is 0 or 1; W is optionally substituted aryl or heteroaryl.

In a preferred embodiment, in the compound of formula (I), aryl is a phenyl ring and heteroaryl is a 5,6-membered monocyclic heteroaryl ring.

In another preferred embodiment, in the compound of formula (I), aryl is a phenyl ring.

In another preferred embodiment, in the compound of formula (I), the heteroaryl is a 5,6-membered monocyclic heteroaryl ring.

In a preferred embodiment, in the compound of formula (I), arylene is a phenyl ring and heteroarylene is a 5,6-membered monocyclic heteroarylene ring.

In another preferred embodiment, in the compound of formula (I), arylene is a phenylene ring.

In another preferred embodiment, in the compound of formula (I), the heteroarylene is a 5,6-membered monocyclic heteroarylene ring.

Preferred groups of compounds of formula (I) are those wherein X and Y are fluorine, n is 0 or 1 and n 'is 0 or 1; Z is a single bond, an -S- group, or an -O group; R ₄ is H, halogen, OH, -SH, -CN and -NR ₆ R ₇ , optionally substituted (C ₁ -C ₆ ) alkylsulfonyl, optionally substituted (C ₁ -C ₆ ) alkylcarbonyl From an optionally substituted (C ₁ -C ₆ ) alkylcarboxyl, optionally substituted (C ₁ -C ₆ ) alkyl and optionally substituted monocyclic (C ₅ -C ₁₀ ) heterocycloalkyl Selected; The R ₂ , R ₆ , R ₇ groups are compounds of formula (IB) as defined for formula (I).

Another preferred group of compounds of formula (I), X and Y are fluorine, R ₁ is _{- (CH 2) n -Z- (} CH 2) n '-R 4 ( wherein, n is 1, Z is Is a single bond, n 'is 0, R ₄ is a -OH group, and R ₂ is a compound of formula (IC) as defined for the compound of formula (I).

[Formula (IC)]

Another preferred group of compounds of formula (I), X and Y are a fluorine, R ₁ is - a _{(CH 2) n -Z- (CH} 2) n '-R 4 ( wherein, n is 0, Z Is -S-, n 'is 1 and R ₄ is a halogen atom) and R ₂ is a compound of formula (ID) as defined for the compound of formula (I).

[Formula (ID)]

Specifically, the halogen atom in R ₄ is fluorine.

Group of compounds of the further preferred formula (I), X and Y are fluorine, R ₁ is _{- (CH 2) n -Z- (} CH 2) n '-R 4 ( wherein, n is 0, Z is Is a single bond, n 'is 1, R ₄ is a halogen atom, and R ₂ is a compound of formula (IE) as defined for the compound of formula (I).

[Formula (IE)]

Specifically, the halogen atom in R ₄ is fluorine.

A preferred group of compounds of formula (I), X and Y are fluorine, R ₂ is _{- (CH 2) s -KA- (} CH 2) t -W or _{- (CH 2) s -K- (} CH 2 ) _t -BW; s is 0 or 1 and K is optionally substituted arylene or heteroarylene; A is selected from the group consisting of a single bond, an -O- group and an -S- group; B is selected from the group consisting of a single bond, an -O- group and an -S- group; t is 0 or 1; W is optionally substituted aryl or heteroaryl; R ₁ is a compound of formula (IF) as defined for compound of formula (I).

In a preferred embodiment for the compound of formula (IF), R ₁ is — (CH ₂ ) _n —Z— (CH ₂ ) _{n ′} —R ₄ , where n is 1 and Z is a single bond, n 'is 0; R ₄ is -OH.

In another preferred embodiment for the compound of formula (IF), R ₁ is-(CH ₂ ) _n -Z- (CH ₂ ) _{n '} -R ₄ , where n is 0 and Z is -S- N 'is 1; R ₄ is a halogen atom.

In another preferred embodiment for the compound of formula (IF), R ₁ is — (CH ₂ ) _n —Z— (CH ₂ ) _{n ′} —R ₄ , where n is 0 and Z is a single bond , n 'is 1; R ₄ is a halogen atom.

It is to be understood that the present invention includes all combinations of the specific and preferred groups and examples described above.

Hereinafter, the compounds of formula (I), (I '), (IA), (IA'), (IB), (IC), (ID), (IE), (IF) and their pharmaceutically acceptable Salts (except intermediate compounds described in chemical methods) are referred to as "compounds of the present invention".

Examples of preferred compounds of the present invention are the compounds listed in the following table, or pharmaceutically acceptable salts thereof.

compound The 6 (4aS, 4bR, 5S, 6aS, 6bR, 9aS, 10aS, 10bS, 12S) -4b, 12-difluoro-8- [4- (4-fluoro-benzyloxy) -benzyl] -5-hydroxy -6b- (2-hydroxy-acetyl) -4a, 6a-dimethyl-4a, 4b, 5,6,6a, 6b, 8,9,9a, 10,10a, 10b, 11,12-tetradecahydro- 7-oxa-8-aza-pentaleno [2,1-a] phenanthren-2-one 7 (4aS, 4bR, 5S, 6aS, 6bR, 9aS, 10aS, 10bS, 12S) -4b, 12-difluoro-8- [4- (4-fluoro-benzyloxy) -benzyl] -5-hydroxy -4a, 6a-dimethyl-2-oxo-2,4a, 4b, 5,6,6a, 8,9,9a, 10,10a, 10b, 11,12-tetradecahydro-7-oxa-8-aza -Pentaleno [2,1-a] phenanthrene-6b-carboxylic acid 8 (4aS, 4bR, 5S, 6aS, 6bR, 9aS, 10aS, 10bS, 12S) -8-((4-fluoro-benzyloxy) -benzyl) -4b, 12-difluoro-5-hydroxy-4a , 6a-dimethyl-2-oxo-2,4a, 4b, 5,6,6a, 8,9,9a, 10,10a, 10b, 11,12-tetradecahydro-7-oxa-8-aza-pental Reno [2,1-a] phenanthrene-6b-carbothioic acid S-fluoromethyl ester 12 (4aS, 4bR, 5S, 6aS, 6bR, 9aS, 10aS, 10bS, 12S) -8- (4-benzyloxy-benzyl) -4b, 12-difluoro-5-hydroxy-6b- (2-hydroxy Roxy-acetyl) -4a, 6a-dimethyl-4a, 4b, 5,6,6a, 6b, 8,9,9a, 10,10a, 10b, 11,12-tetradecahydro-7-oxa-8-aza Pentaleno [2,1-a] phenanthren-2-one 13 (4aS, 4bR, 5S, 6aS, 6bR, 9aS, 10aS, 10bS, 12S) -8- (4-benzyloxy-benzyl) -4b, 12-difluoro-5-hydroxy-4a, 6a-dimethyl- 2-oxo-2,4a, 4b, 5,6,6a, 8,9,9a, 10,10a, 10b, 11,12-tetradecahydro-7-oxa-8-aza-pentaleno [2,1 -a] phenanthrene-6b-carboxylic acid 14 (4aS, 4bR, 5S, 6bR, 9aS, 10aS, 10bS, 12S) -8-((S) -4-benzyloxy-benzyl) -4b, 12-difluoro-5-hydroxy-4a, 6a- Dimethyl-2-oxo-2,4a, 4b, 5,6,6a, 8,9,9a, 10,10a, 10b, 11,12-tetradecahydro-7-oxa-8-aza-pentaleno [2 , 1-a] phenanthrene-6b-carbothioic acid S-fluoromethyl ester 34 (4aS, 4bR, 5S, 6aS, 6bR, 9aS, 10aS, 10bS, 12S) -4b, 12-difluoro-5-hydroxy-
6b- (2-hydroxy-acetyl) -4a, 6a-dimethyl-8- [4- (4-hydroxy-phenylsulfanylmethyl) -benzyl] -4a, 4b, 5,6,6a, 6b, 8 , 9,9a, 10,10a, 10b, 11,12-tetradecahydro-7-oxa-8-aza-pentaleno [2,1-a] phenanthren-2-one

(continue)

37 (4aS, 4bR, 5S, 6aS, 6bR, 9aS, 10aS, 10bS, 12S) -4b, 12-difluoro-5-hydroxy-
6b- (2-hydroxy-acetyl) -4a, 6a-dimethyl-8- [4- (4-hydroxy-phenylsulfanylmethyl) -phen
Nil] -4a, 4b, 5,6,6a, 6b, 8,9,9a, 10,10a, 10b, 11,12-tetradecahydro-7-jade
Sa-8-aza-pentaleno [2,1-a] phenanthren-2-one 36 (4aS, 4bR, 5S, 6aS, 6bR, 9aS, 10aS, 10bS, 12S) -4b, 12-difluoro-5-hydroxy-4a, 6a-dimethyl-8- [4- (4-hydroxy- Phenylsulfanylmethyl) -benzyl] -2-oxo-2,4a, 4b, 5,6,6a, 8,9,9a, 10,10a, 10b, 11,12- tetradecahydro-7-oxa-8 Aza-pentaleno [2,1-a] phenanthrene-6b-carbothioic acid S-fluoromethyl ester 35 (4aS, 4bR, 5S, 6aS, 6bR, 9aS, 10aS, 10bS, 12S) -4b, 12-difluoro-5-hydroxy-6b- (2-hydroxy-acetyl) -4a, 6a-dimethyl- 8- (5-methyl-2-thiophen-2-yl-oxazol-4-ylmethyl) -4a, 4b, 5,6,6a, 6b, 8,9,9a, 10,10a, 10b, 11 , 12-tetradecahydro-7-oxa-8-aza-pentaleno [2,1-a] phenanthren-2-one 50 (4aS, 4bR, 5S, 6aS, 6bR, 9aS, 10aS, 10bS, 12S) -4b, 12-difluoro-5-hydroxy-4a, 6a-dimethyl-8- [4- (4-hydroxy- Phenylsulfanylmethyl) -phenyl] -2-oxo-2,4a, 4b, 5,6,6a, 8,9,9a, 10,10a, 10b, 11,12- tetradecahydro-7-oxa-8 Aza-pentaleno [2,1-a] phenanthrene-6b-carbothioic acid S-fluoromethyl ester 52 (4aS, 4bR, 5S, 6aS, 6bR, 9aS, 10aS, 10bs, 12S) -4b, 12-difluoro-5-hydroxy-6b- (2-hydroxy-acetyl) -4a, 6a-dimethyl- 8- (4-thiophen-2-yl-phenyl) 4a, 4b, 5,6,6a, 6b, 8,9,9a, 10,10a, 10b, 11,12-tetradecahydro-7-oxa- 8-aza-pentaleno [2,1-a] phenanthren-2-one 38 (4aS, 4bR, 5S, 6aS, 6bR, 9aS, 10aS, 10bs, 12S) -8-biphenyl-4-yl-4b, 12-difluoro-5-hydroxy-6b- (2-hydroxy- Acetyl) -4a, 6a-dimethyl-4a, 4b, 5,6,6a, 6b, 8,9,9a, 10,10a, 10b, 11,12-tetradecahydro-7-oxa-8-aza-pental Reno [2,1-a] phenanthrene-2-one 39 (4aS, 4bR, 5S, 6aS, 6bR, 9aS, 10aS, 10bs, 12S) -4b, 12-difluoro-5-hydroxy-6b- (2-hydroxy-acetyl) -4a, 6a-dimethyl- 8- (4-methoxyphenylsulfanylmethyl) -4a, 4b, 5,6,6a, 6b, 8,9,9a, 10,10a, 10b, 11,12-tetradecahydro-7-oxa-8 Aza-pentaleno [2,1-a] phenanthren-2-one 40 (4aS, 4bR, 5S, 6aS, 6bR, 9aS, 10aS, 10bs, 12S) -8- (4-benzyl-phenyl) -4b, 12-difluoro-5-hydroxy-6b- (2-hydroxy -Acetyl) -4a, 6a-dimethyl-4a, 4b, 5,6,6a, 6b, 8,9,9a, 10,10a, 10b, 11,12-tetradecahydro-7-oxa-8-aza- Pentaleno [2,1-a] phenanthren-2-one 41 (4aS, 4bR, 5S, 6aS, 6bR, 9aS, 10aS, 10bs, 12S) -4b, 12-difluoro-5-hydroxy-6b- (2-hydroxy-acetyl) -4a, 6a-dimethyl- 8- (4-pyridin-4-ylmethyl-phenyl) -4a, 4b, 5,6,6a, 6b, 8,9,9a, 10,10a, 10b, 11,12-tetradecahydro-7-oxa -8-aza-pentaleno [2,1-a] phenanthren-2-one

(continue)

42 (4aS, 4bR, 5S, 6aS, 6bR, 9aS, 10aS, 10bs, 12S) -4b, 12-difluoro-8- [4- (4-fluoro-benzylsulfanyl) -phenyl] -5-hydr Hydroxy-6b- (2-hydroxy-acetyl) -4a, 6a-dimethyl-4a, 4b, 5,6,6a, 6b, 8,9,9a, 10,10a, 10b, 11,12-tetradecahydro -7-oxa-8-aza-pentaleno [2,1-a] phenanthren-2-one 43 (4aS, 4bR, 5S, 6aS, 6bR, 9aS, 10aS, 10bs, 12S) -8- [4- (4-chloro-phenoxymethyl) -phenyl] -4b, 12-difluoro-5-hydroxy -6b- (2-hydroxy-acetyl) -4a, 6a-dimethyl-4a, 4b, 5,6,6a, 6b, 8,9,9a, 10,10a, 10b, 11,12-tetradecahydro- 7-oxa-8-aza-pentaleno [2,1-a] phenanthren-2-one 44 (2-hydroxy-acetyl) -8- [4- ((4-fluoro- 4-methoxy-4-phenoxymethyl) -phenyl] -4a, 6a-dimethyl-4a, 4b, 5,6,6a, 6b, 8,9,9a, 10,10a, 10b, 11,12-tetra Decahydro-7-oxa-8-aza-pentaleno [2,1-a] phenanthren-2-one 45 (4aS, 4bR, 5S, 6aS, 6bR, 9aS, 10aS, 10bs, 12S) -8-biphenyl-3-yl-4b, 12-difluoro-5-hydroxy-6b- (2-hydroxy- Acetyl) -4a, 6a-dimethyl-4a, 4b, 5,6,6a, 6b, 8,9,9a, 10,10a, 10b, 11,12-tetradecahydro-7-oxa-8-aza-pental Reno [2,1-a] phenanthrene-2-one 46 (4aS, 4bR, 5S, 6aS, 6bR, 9aS, 10aS, 10bs, 12S) -8- [4- (3-chloro-phenoxymethyl) -phenyl] -4b, 12-difluoro-5-hydroxy -6b- (2-hydroxy-acetyl) -4a, 6a-dimethyl-4a, 4b, 5,6,6a, 6b, 8,9,9a, 10,10a, 10b, 11,12-tetradecahydro- 7-oxa-8-aza-pentaleno [2,1-a] phenanthren-2-one; 47 (4aS, 4bR, 5S, 6aS, 6bR, 9aS, 10aS, 10bs, 12S) -4b, 12-difluoro-5-hydroxy-6b- (2-hydroxy-acetyl) -4a, 6a-dimethyl- 8- (3-p-tolyloxymethyl-phenyl) -4a, 4b, 5,6,6a, 6b, 8,9,9a, 10,10a, 10b, 11,12- tetradecahydro-7-oxa- 8-aza-pentaleno [2,1-a] phenanthren-2-one 48 (4aS, 4bR, 5S, 6aS, 6bR, 9aS, 10aS, 10bs, 12S) -8- [4- (3-chloro-benzylsulfanyl) -phenyl] -4b, 12-difluoro-5-hydroxy -6b- (2-hydroxy-acetyl) -4a, 6a-dimethyl-4a, 4b, 5,6,6a, 6b, 8,9,9a, 10,10a, 10b, 11,12-tetradecahydro- 7-oxa-8-aza-pentaleno [2,1-a] phenanthren-2-one 49 (4aS, 4bR, 5S, 6aS, 6bR, 9aS, 10aS, 10bS, 12S) -4b, 12-difluoro- Phenyl] -4a, 6a-dimethyl-2-oxo-2,4a, 4b, 5,6,6a, 8,9,9a, 10,10a, 10b, 11,12-tetradecahydro-7-oxa-8 Aza-pentaleno [2,1-a] phenanthrene-6b-carboxylic acid 51 (4aS, 4bR, 5S, 6aS, 6bR, 9aS, 10aS, 10bS, 12S) -4b, 12-difluoro- Benzyl] -4a, 6a-dimethyl-2-oxo-2,4a, 4b, 5,6,6a, 8,9,9a, 10,10a, 10b, 11,12-tetradecahydro-7-oxa-8 Aza-pentaleno [2,1-a] phenanthrene-6b-carboxylic acid

According to a method analogous to that described in the present specification, the following compounds, or pharmaceutically acceptable salts thereof, can also be obtained in the present invention:

(4aS, 4bR, 5S, 6aS, 6bR, 9aS, 10aS, 10bS, 12S) -4b, 12-difluoro-5-hydroxy-6b- (2-hydroxy-acetyl) -4a, 6a-dimethyl- 8- (4-p-tolylsulfanylmethyl-benzyl) -4a, 4b, 5,6,6a, 6b, 8,9,9a, 10,10a, 10b, 11,12-tetradecahydro-7-oxa -8-aza-pentaleno [2,1-a] phenanthren-2-one;

(4aS, 4bR, 5S, 6aS, 6bR, 9aS, 10aS, 10bs, 12S) -4b, 12-difluoro-5-hydroxy-4a, 6a-dimethyl-2-oxo-8- (1-phenyl- 1H-Pyrrole-2-yl) -2,4a, 4b, 5,6,6a, 8,9,9a, 10,10a, 10b, 11,12-tetradecahydro-7-oxa-8-aza-pental Leno [2,1-a] phenanthrene-6b-carbothioic acid S-fluoromethyl ester;

(4aS, 4bR, 5S, 6aS, 6bR, 9aS, 10aS, 10bS, 12S) -8- (1-benzyl-1H-pyrrol-2-yl) -4b, 12-difluoro-5-hydroxy-4a , 6a-dimethyl-2-oxo-2,4a, 4b, 5,6,6a, 8,9,9a, 10,10a, 10b, 1 1,12-tetradecahydro-7-oxa-8-aza- Pentaleno [2,1-a] phenanthrene-6b-carbothioic acid S-fluoromethyl ester;

(4aS, 4bR, 5S, 6aS, 6bR, 9aS, 10aS, 10bS, 12S) -4b, 12-difluoro-5-hydroxy-4a, 6a-dimethyl-2-oxo-8- (5-phenyl- Oxazol-2-yl) -2,4a, 4b, 5,6,6a, 8,9,9a, 10,10a, 10b, 11,12-tetradecahydro-7-oxa-8-aza-pentaleno [2,1-a] phenanthrene-6b-carbothioic acid S-fluoromethyl ester;

(4aS, 4bR, 5S, 6aS, 6bR, 9aS, 10aS, 10bS, 12S) -4b, 12-difluoro-5-hydroxy-4a, 6a-dimethyl-2-oxo-8- (2-thiophene 2-yl-phenyl) -2,4a, 4b, 5,6,6a, 8,9,9a, 10,10a, 10b, 11,12-tetradecahydro-7-oxa-8-aza-pentaleno [2,1-a] phenanthrene-6b-carbothioic acid S-fluoromethyl ester;

(4aS, 4bR, 5S, 6aS, 6bR, 9aS, 10aS, 10bS, 12S) -4b, 12-difluoro-5-hydroxy- -Methyl-2-thiophen-2-yl-oxazol-4-ylmethyl))-2,4a, 4b, 5,6,6a, 8,9,9a, 10,10a, 10b, 11,12- Tetradecahydro-7-oxa-8-aza-pentaleno [2,1-a] phenanthrene-6b-carbothioic acid S-fluoromethyl ester;

(4aS, 4bR, 5S, 6aS, 6bR, 9aS, 10aS, 10bS, 12S) -4b, 12-difluoro-5-hydroxy-4a, 6a-dimethyl-2-oxo-8- (4-benzyloxy -Phenyl) -2,4a, 4b, 5,6,6a, 8,9,9a, 10,10a, 10b, 11,12-tetradecahydro-7-oxa-8-aza-pentaleno [2,1 -a] phenanthrene-6b-carbothioic acid S-fluoromethyl ester;

(4aS, 4bR, 5S, 6aS, 6bR, 9aS, 10aS, 10bS, 12S) -4b, 12-difluoro-5-hydroxy-4a, 6a- -Fluoro-benzyloxy) -phenyl] -2,4a, 4b, 5,6,6a, 8,9,9a, 10,10a, 10b, 11,12-tetradecahydro-7-oxa-8-aza -Pentaleno [2,1-a] phenanthrene-6b-carbothioic acid S-fluoromethyl ester.

The invention also provides a pharmaceutical composition comprising a compound of the invention and one or more pharmaceutically acceptable carriers and / or excipients.

The compounds of the present invention may be administered alone or in combination with other pharmaceutically active ingredients, including those presently used for the treatment of respiratory diseases. Agonists, antimuscarinic agents, corticosteroids, mitogen-activated protein kinase (P38 MAP kinase) inhibitors, nuclear factor kappa-B kinase subunit beta (IKK2) inhibitors, human neutrophil elastase (HNE) inhibitors, phos Podiesterase 4 (PDE4) inhibitors, leukotriene modulators, nonsteroidal anti-inflammatory agents (NSAIDs) and mucus modulators.

The invention also relates to compounds of the invention, carmoterol, GSK-642444, indacaterol, milveterol, arfooterol, formoterol, sal Salbutamol, levalbuterol, terbutaline, AZD-3199, BI-1744-CL, LAS-100977, bambuterol, isoproterenol, procatethe A combination of β2-agonists selected from the group consisting of procaterol, clenbuterol, reproterol, fenoterol and ASF-1020 and salts thereof is provided.

The invention also consists of aclidinium, thiopropium, ipratropium, trospium, glycopyrronium and oxytropium salts Provided are combinations of an antimuscarinic agent selected from the group with a compound of the present invention.

 The present invention relates to compounds of formula (I), AN-2728, AN-2898, CBS-3595, apremilast, ELB-353, KF-66490, K-34, LAS-37779, IBFB-211913 , AWD-12-281, cifamfylin, cilomilalast, roflumilast, BAY19-8004 and SCH-351591, AN-6415, indus-82010, TPI-PD3, ELB-353 Also provided are combinations of PDE4 inhibitors selected from the group consisting of, CC-11050, GSK-256066, oglemilast, OX-914, tetomilast, MEM-1414 and RPL-554.

The present invention relates to the compounds of the present invention, semapimod, talmapimod, pirfenidone, PH-797804, GSK-725, minocaine and losmapimod. And P38 MAP inhibitors selected from the group consisting of these salts.

In a preferred embodiment, the present invention provides a combination of a compound of the invention with an IKK2 inhibitor.

The present invention also provides compounds of the present invention, AAT, ADC-7828, Airiva, TAPI, AE-3763, KRP-109, AX-9657, POL-6014, AER-002, AGTC-0106, Res Respriva, AZD-9668, zemaira, AAT IV, PGX-100, elafin, SPHD-400, prolastin C and inhaled prolastin inhaled A combination of HNE inhibitors selected from the group consisting of

The invention also provides a combination of a compound of the invention with a leukotriene modulator selected from the group consisting of montelukast, zafirlukast and pranlukast.

The present invention provides a combination of a compound of the present invention with an NSAID selected from the group consisting of ibuprofen and ketoprofen.

The invention also relates to the group consisting of INS-37217, diquafosol, sibenadet, CS-003, talnetant, DNK-333, MSI-1956 and gefitinib. Provided are combinations of mucus modulators selected with the compounds of the present invention.

The invention also provides a compound of the invention for use as a medicament.

The invention also relates to the use of the compounds of the invention for reducing the number, activity and migration of inflammatory cells in vitro and / or in vivo.

The invention also relates to the use of the compounds of the invention in the prevention or treatment of any disease involving the reduction of the number, activity and migration of inflammatory cells.

In another aspect of the invention, the invention provides the use of a compound of the invention for the prevention and / or treatment of any disease involving reduction in the number, activity and migration of inflammatory cells.

Specifically, the compounds of the present invention, in combination with one or more active ingredients or in their sole form, may be administered for the prevention and / or treatment of respiratory diseases characterized by airway obstruction such as asthma and COPD.

In another aspect of the invention, the invention provides the use of a compound of the invention for the manufacture of a medicament for the prevention and / or treatment of a disease in which a reduction in the number, activity and migration of inflammatory cells is involved.

Moreover, the present invention provides methods for the prevention and / or treatment of any disease involving reduction in the number, activity and migration of inflammatory cells, wherein the method provides for the treatment of a compound of the invention in a patient in need thereof. Administering an effective amount.

The invention also provides pharmaceutical preparations of the compounds of the invention suitable for inhalation, injection, oral or nasal administration.

Inhalable preparations include inhaled powders, propeller-containing metered aerosols or propeller-free inhalation formulations.

The present invention also relates to a device which may be a single or multiple dose dry powder inhaler, a metered dose inhaler or a nebulizer, in particular a soft mist nebulizer, etc. comprising a compound of the invention.

The invention also provides a pharmaceutical composition of a compound of the invention in a single form, combined or not combined with one or more pharmaceutically acceptable carriers and / or excipients, single dose or multiple dose dry powder inhalers, A kit comprising a device, which may be a metered dose inhaler or nebulizer.

The compounds of the present invention can be prepared according to conventional methods and techniques or by various synthetic steps which can be carried out as described below.

In one aspect, the invention provides a process for the preparation of a compound of the invention and an intermediate thereof.

In one embodiment, the present invention provides a compound of formula (I ') wherein R ₁ =-(CH ₂ ) _n -Z- (CH ₂ ) _n' -R ₄ , n = 1, n '= 0 , Z and R ₄ is a method for producing the same) as described above (to provide a route a) of Scheme 1, in this method, 2-hydroxy-acetyl group of the hydroxyl moiety of the position 6b of the compound of formula (VI) Is converted to the leaving group (LG) of the compound of Scheme (XI), where LG is substituted with a suitable nucleophile to yield the compound of formula (I) as described above.

The invention also relates to compounds of formula (I ') wherein R ₁ =-(CH ₂ ) _n -Z- (CH ₂ ) _n' -R ₄ , n and n '= 0, Z and R ₄ are as defined above. And the route B1 of Scheme 1 , wherein the method comprises reacting a compound of formula (VI) to produce a compound of formula (XII),

Subsequently, treating the compound of formula (XII) with at least one equivalent of an acid activator and then treating with a nucleophile to produce a compound of formula (I) as described above.

For those skilled in the art, compounds of formula (I ') corresponding to compounds of formula (XII) as described above, wherein R ₁ =-(CH ₂ ) _n -Z- (CH ₂ ) _n' It will be apparent that -R ₄ , n = n '= 0, Z = single bond, R ₄ = -OH, is a useful intermediate for the synthesis of other compounds of the invention according to the synthetic methods described herein.

The invention also relates to compounds of formula (I ') wherein R ₁ =-(CH ₂ ) _n -Z- (CH ₂ ) _n' -R ₄ , n = n '= 0, Z = S, R ₄ = As described above) ( Route B2 of Scheme 1 ), which method

Reacting the compound of formula (VI) under oxidizing conditions to produce an intermediate of formula (XII),

Then converting it to a compound of formula (XIII),

Alkylating the compound of formula (XIII) to produce a compound of formula (I ′) as described above.

The invention also relates to a process for the preparation of a compound of formula (VI) ( root A1 of Scheme 1 ),

Reacting a compound of formula (IV) with N-tetrahydropyranyl hydroxylamine (HO-NH-THP) to produce a compound of formula (V),

Further functionalizing the compound of formula (V) with the introduction of an R ₂ group as described above,

Removing the acetyl protecting group from the hydroxy group to produce a compound of formula (VI) as described above.

The present invention relates to a further process for the preparation of the compound of formula (VI) ( route A2 of Scheme 1 ), wherein the compound of formula (VII) is reacted with the compound of formula (X) and para formaldehyde, Producing the compound of (VI).

The invention also relates to another process for the preparation of compounds of formula (VI) ( root A3 of Scheme 1 ),

Reacting a compound of formula (VII) with N-tetrahydropyranyl hydroxylamine (HO-NH-THP) to produce a compound of formula (VIII),

Protecting a compound of formula (VIII) to produce a compound of formula (IX),

Then further functionalizing the compound of formula (IX),

Finally removing the protecting group from the hydroxy group to produce a compound of formula (VI) as described above.

The invention also relates to compounds of formula (I ') wherein R ₁ =-(CH ₂ ) _n -Z- (CH ₂ ) _n' -R ₄ , n and n ' = 0, Z = O, R ₄ = A process for the preparation of Ac), wherein the process ( root C of Scheme 1 ) comprises reacting an intermediate of formula (IV) with hydroxylamine and paraformaldehyde of formula (X).

The invention also relates to compounds of formula (I ') wherein R ₁ =-(CH ₂ ) _n -Z- (CH ₂ ) _n' -R ₄ , n = 0, n ' = 1, R ₄ = F, Z is a method of making a single bond, which is the route E in Scheme 1

Reacting the compound of formula (VII) with mesyl chloride and DIPEA in dry acetonitrile,

In situ addition of tetra-n-butylammonium fluoride (TBAF) and KI,

-Cycloaddition of HO-NH-THP with paraformaldehyde with the obtained intermediate (XV),

Followed by nitrogen functionalization to produce the compound of formula (I) as described above.

In a preferred embodiment of the present invention, all the methods described herein are carried out with compounds and intermediates wherein X and Y are fluorine.

From the foregoing, it will be apparent to one skilled in the art that any possible stereoisomer of formula (I) may also be produced by selecting starting materials with suitable stereochemical arrangements.

Some methods that can be used to prepare compounds of formula (I ') are described in Scheme 1, which may also be applied to compounds of formula (I).

[Reaction Scheme 1]

The method for producing the compound of the present invention

According to certain embodiments, the compounds of the present invention may be prepared according to different methods than those described in Scheme 1 depending on the properties of the substituents R ₁ and R ₂ .

Root A1

The reaction of N-tetrahydropyranyl hydroxylamine (HO-NH-THP) with a compound of formula (IV) to prepare a compound of formula (V) is performed in a protic solvent such as EtOH in the range of 80 to 100 ° C. It can be done conveniently at temperature. THP protecting groups are removed directly under reaction conditions.

The compounds are further functionalized with alkyl halides, acyl halides, isocyanates, carbamoyl chlorides or sulfonyl chlorides using conventional methods (J. Med. Chem., 379-388, 1995; JC S. Chem. Comm , 256-257, 1985), compounds of formula (VI) can be produced. The reaction is usually carried out in a solvent such as dichloromethane (DCM) or tetrahydrofuran (THF) and proceeds in a temperature range from room temperature (RT) to reflux. Basics such as triethylamine or diisopropylethylamine may also be required to promote the reaction. The reaction with aryl halides can be carried out under copper catalyst N-arylation of isoxazolidine as known (Bioorg. Med. Chem. Lett., 2834, 2005). Acetyl esters are readily hydrated using standard conditions of deacetylation of alcohols, such as treating the compound with a base such as sodium or potassium hydroxide or potassium carbonate in a suitable solvent (eg methanol or ethanol). Can be. This reaction usually proceeds at room temperature for 1 to 5 hours to produce the compound of formula (VI).

Compounds of formula (IV) may be conveniently prepared according to standard procedures as reported in the literature. For example, they can be prepared by treating a compound of formula (III) with a base such as potassium acetate. This reaction is usually carried out in a suitable polar solvent such as dimethyl formamide (DMF) and typically proceeds at a temperature of 80 to 110 ° C. for 0.5 to 4 hours.

Compounds of formula (III) can be readily prepared from known compounds by well-known methods, starting with compounds of formula (II) (J. Med. Chem. 1982, 25, 1492-1495).

Root A2

Alternatively, the compound of formula (VI) may be reacted with a compound of formula (X) in the presence of paraformaldehyde, using a known method for isooxazolidine formation, by cycloaddition of nitrone. VII) by reacting the compound (J. Med. Chem., 25, 1492-1495, 1982). This reaction is conveniently carried out in a protic solvent such as ethanol at a temperature in the range from 80 to 100 ° C. The hydroxyl amine of the formula (X) may be commercially available or used to reduce the oxime with a reducing agent such as, for example, a borane pyridine complex (J. Med. Chem., 40, 1955-1968, 1997), or an alkyl halide or the like. Can be prepared using a method well known in the art, such as reacting an appropriate alkylating agent with O-tetrahydropyranyl hydroxylamine (Chem. Pharm. Bull., 46, 966-972, 1998). .

Compounds of formula (VII) can be prepared by hydrating a compound of formula (IV). This reaction is preferably carried out by adding compound (IV) to an enzyme such as a fixed lipase from Candida antarctica (Sigma Aldrich) (Tetrahedron, 50, 13165-13172, 1994).

Root A3

Compounds of formula (VIII) can be prepared starting by reacting HO-NH-THP with compounds of formula (VII). This reaction can be conveniently carried out in a proton solvent such as EtOH or in dioxane at a temperature in the range from 80 to 100 ° C. THP protecting groups are removed directly at reaction conditions. The obtained compound of formula (VIII) is conveniently and selectively protected by treatment with dihydropyran at 0 ° C. to room temperature in a suitable solvent such as DCM or THF to obtain a compound of formula (IX). This reaction is completed in 0.5 to 3 hours. Compounds of formula (IX) may be further functionalized with alkyl halides, acyl halides, isocyanates, carbamoyl chlorides or sulfonyl chlorides, as described for route A1. THP protecting groups can be easily removed by treating HCl protected intermediates in a suitable solvent such as THF or dioxane. This reaction usually proceeds for 1 to 15 hours at room temperature to yield the compound of formula (VI).

Root A

Converting the hydroxyl group of the 2-hydroxy acetyl moiety at the 6b position of the compound of formula (VI) to the leaving group (LG) of the compound of formula (XI) is methane in a suitable solvent such as pyridine. This can be done by treating the compound of formula (VI) with sulfonyl chloride or p-toluenesulfonyl chloride (March's, "Advanced Organic Chemistry", Wiley-Interscience). This reaction is usually carried out at room temperature for 1 to 5 hours.

LG of a compound of formula (XI) is the compound of halide anions, are easily substituted with an alcohol, thiol, tea nucleophile such mistake, amines, amides and cover Canyon, formula (I) and formula (I ') (wherein, R ₁ =-(CH ₂ ) _n -Z- (CH ₂ ) _{n '} -R ₄ , n = 1, n' = 0, Z = single bond, R ₄ = as described above. Chem., 1042, 1999; J. Steroid. Biochem. 13, 311-322, 1980). This reaction is usually carried out in a suitable solvent such as DCM, THF or DMF at a temperature in the range of 0 to 80 ° C. for 1 to 5 hours and can be promoted by a base such as sodium or potassium carbonate or sodium hydride. The resulting product can be further functionalized by modifying the moiety introduced by the nucleophilic substitution reaction described above.

Root B

It is a reaction that reacts a compound of formula (VI) under well-known oxidation conditions to produce an intermediate of formula (XII). This reaction is usually carried out in an open base of an aqueous solution of an inorganic base such as sodium or potassium hydroxide, in a suitable solvent such as THF, at room temperature for 12 to 48 hours.

Root B1

By treating the acid of formula (XII) with at least one equivalent of an acid activator such as carbonylimidazole, the intermediate of formula (XII) is subjected to the compounds of formulas (I) and (I ′), wherein R ₁ =-( CH ₂ ) _n -Z- (CH ₂ ) _{n '} -R ₄ , n = and n' = 0, Z and R ₄ = as described above. This reaction is usually carried out in a suitable polar solvent such as DMF at a temperature of 0 to 80 ° C. for 1 to 2 hours. The activated acid can react with nucleophiles such as alcohols, thiols, thioacids and amines. This reaction can be promoted by a base such as sodium or potassium carbonate, sodium hydride, and proceeds at 0-20 ° C. for 1-24 hours.

Alternatively, the intermediate of formula (XII) can be converted to the corresponding acyl chloride under well known conditions using oxalyl chloride in a suitable solvent such as DCM. Activated intermediates include alcohols such as alkyl, aryl and heteroaryl cuprates or other organometallic compounds, thiols, thioacids, amines and carbanions, such as those reported in the literature, which are known to be suitable for the conversion of acyl chlorides to the corresponding ketones. Can react with nucleophiles.

Root B2

The conversion of an intermediate of formula (XII) to a compound of formula (XIII), derived from the reaction of carbonyldiimidazole with acid (XII), followed by reaction with sodium salt of thioacetic acid and / or anhydrous hydrogen sulfide Reaction. This reaction is usually carried out by adding a preformed salt solution in the reaction solvent to the activated acid solution at a temperature in the range from 0 to 20 ° C. Thioic acid intermediates (XIII) are readily formed by in situ reaction with alkylating agents such as bromoalkanes, which are thioesters of formula (I) and (I '), wherein R ₁ =-(CH ₂ ) _n -Z- (CH ₂ ) _{n '} -R ₄ , n = and n' = 0, Z = S, R ₄ = as described above. Selection of suitable bromoalkanes, such as bromo-chloromethane, is carried out using compounds of formulas (I) and (I '), wherein R ₁ =-(CH ₂ ) _n -Z- (CH ₂ ) _n' -R ₄ , n = and n '= 0, Z = S, R ₄ = as described above), which can be further modified. For example, reacting these compounds (where R ₄ is chloromethyl) with potassium iodide and then treating with silver fluoride gives compounds of formulas (I) and (I ') (R ₃ = fluoromethyl ) Enables the production of These reactions are well known to those skilled in the art (J. Med. Chem., 37, 3717-3729, 1994).

Root C

The reaction of the intermediate of formula (IV) with the hydroxylamine of formula (X) in the presence of paraformaldehyde using a known procedure for isooxazolidine formation by cycloaddition of nitrons. This reaction is conveniently carried out in a protic solvent such as ethanol. This reaction is conveniently carried out at high temperatures, such as at 60 to 85 ° C., so that compounds of formula (I) and (I ′) are present, wherein R ₁ =-(CH ₂ ) _n -ZR ₄ , n = 1, Z = O, R ₄ = Ac).

Intermediates of formula (XIV) are compounds of formula (I) and (I ′), wherein R ₁ =-(CH ₂ ) _n -ZR ₄ , n = 1, and Z = O, R ₄ = Ac, X = H) can be prepared by treating with methanesulfonyl chloride in a suitable solvent such as DMF in the presence of a base such as pyridine. The reaction proceeds at a temperature in the range of 80 to 100 ° C. for 1 to 5 hours.

Compounds of formula (I) and (I ') are reacted under well known conditions for the preparation of chlorohydrin starting from the alkene, wherein R ₁ =-(CH ₂ ) _n − ZR ₄ , where n = 1, and Z = 0, R ₄ = H and X = Cl). This reaction involves the use of a chlorinating agent such as N-chlorosuccinimide or dichloro-5,5-dimethylhydantoin and is promoted by an acid such as perchloric acid. This reaction is usually carried out in a polar solvent such as THF in the temperature range of 0 to 20 ° C. for 1 to 4 hours. Acetyl esters of compounds of formula (XIV) can be readily hydrated by treating the compound with a base such as sodium or potassium carbonate in a solvent such as methanol or ethanol, using standard conditions suitable for deacetylation of the alcohol. . This reaction usually proceeds for 0.5 to 2 hours at low temperatures ranging from 0 to 20 ° C.

Root D

The intermediate of formula (VI) is reacted with acyl chloride using procedures well known in the art. The reaction is conveniently carried out in DCM as solvent in the presence of a base such as triethylamine for 20-50 hours at room temperature. This procedure comprises a compound of formula (I ') wherein R ₁ =-(CH ₂ ) _n -Z- (CH ₂ ) _n' -R ₄ , n = 1, n '= 0, Z = O, R ₃ = As described above) can be made possible.

Root E

Reaction of mesyl chloride and N, N-diisopropylethylamine (DIPEA) with compound (VII) in dry acetonitrile. The introduction of fluorine atoms can then be conveniently carried out by in situ addition of tetra-n-butylammonium fluoride (TBAF) and KI and heating for 8-20 hours. In the presence of paraformaldehyde under the well-known conditions set forth in route C, the cycloaddition reaction of the hydroxylamine of formula (X) with the intermediate (XV) obtained is carried out to the compound of formula (I ′) wherein R ₁ = -(CH ₂ ) _n -Z- (CH ₂ ) _{n '} -R ₄ , n = 0, n' = 1, Z = single bond, R ₄ = F, R ₂ = as described above).

The hydroxylamines of formula (X) are commercially available or may be prepared according to other synthetic methods (some are well known).

In one aspect of the invention, a process for the synthesis of hydroxylamine of formula (X) is provided as described in Scheme 2.

[Reaction Scheme 2]

Root F

In the presence of triethylamine, the reaction for preparing the oxime of formula (XVII) by reacting hydroxylamine hydrochloride (NH ₂ OH HCl) with a compound of formula (XVI) is carried out at a temperature ranging from room temperature to 50 ° C. It can conveniently be carried out in DCM as a solvent.

These compounds (oximes of formula (XVII)) are reacted with hydroxylamines of formula (Xa), wherein R _x and R, using a reducing agent such as borane pyridine complex and HCl in polar protic solvents such as ethanol at room temperature _y can be reduced to different interpretations within the scope of the invention (Tetrahedron 1992, Vol. 47, N ° 17, 3557-3570; J. Med. Chem. 1997, 40, 1955-1968). Compounds of formula (XVI) can be obtained by the oxidation of compounds of formula (XVIII) by commercially or well known procedures (eg Swern oxidation: JACS, 2005, 127, 29, 10396).

Root G

Alternatively, the compounds of formula (Xa) may be used to generate intermediates of formula (XX) using well known methods (JACS 2000, 122, 18, 4522; Tetrahedron 1999, 55, 41, 12069). Activated compounds of formula (XIX), where LG is a suitable leaving group such as, for example, halides (Cl, Br, or I), mesylate, tosylate or other leaving groups, and O-tetrahydropyranyl hydroxylamine Following the reaction of (NH ₂ OTHP), it can be prepared by deprotecting the THP protecting group. The substitution reaction is conveniently carried out in DMF, ethanol or acetonitrile as a solvent in the presence of other kinds of bases such as K ₂ CO ₃ or DIPEA at temperatures ranging from room temperature to 80 ° C. Compounds of formula (XIX) are prepared from alcohols of formula (XVIII) and are prepared by converting hydroxyl groups to suitable leaving groups by known procedures, or may be purchased and used. For example, mesylate can be conveniently obtained from mesyl chloride and TEA and alcohol (XVIII) in DCM (Organic Letters 2002, vol. 4, N ° 15, 2485).

Root H

The hydroxylamine of formula (Xb), wherein R ₂ is optionally substituted aryl or heteroaryl, can be prepared starting from the corresponding nitro-aryl or nitro-heteroaryl compound. For example, the nitro compound (XXI) can be conveniently reduced to hydroxylamine at room temperature using BiCl ₃ and KBH ₄ in a polar protic solvent such as ethanol (Synthetic Communications 1997, Vol. 27, N ° 20, 3497-3504). Alternatively, aryl or heteroaryl hydroxylamine (Xb) is used as hydrazine hydrate (J. Med. Chem. 1987, 30, 2, 400; Eur. J. in the presence of rhodinium on carbon in tetrahydrofuran as solvent. Org.Chem. 2006, 16,3707), or hydrazine (Synthesis 1984, 11, 938-941), nitro compound (XXI) in the presence of Raney nickel in a suitable solvent mixture such as ethanol and dichloromethane. It can be conveniently obtained by reducing the If necessary, in this procedure, it is necessary to adjust the temperature to 0 to 10 ° C. Finally, another convenient reduction method for producing compounds of formula (Xb) involves the reduction of formula (XXI) with Zn and NH ₄ Cl in different polar solvents such as acetone or ethanol (Tetrahedron Letters 2005, Vol. .46, N ° 35, 5913-5918; Joc 1982, 47, 7, 1171).

Root L

Alternatively, the aryl or heteroaryl hydroxylamine of formula (Xb) as described above can be substituted with a chloride or fluoride that lacks aryl or heteroaryl electrons with hydroxylamine using methods that are apparent to those skilled in the art. It can manufacture by nucleophilic aromatic substitution. For example, the reaction of a compound of formula (XXII), wherein Y is a suitable leaving group such as fluorine or chlorine, and an aqueous solution of hydroxylamine in ethanol (J. Med. Chem. 2009, 52, 19, 5974) Generate hydroxylamine of Xb). This reaction is carried out at reflux for 6 to 10 hours. Other methods of reacting suitable aryl or heteroaryl electron deficient chlorides or fluorides with hydroxylamine hydrochloride in polar protic solvents such as isopropanol are also disclosed (WO 2006/74187). This reaction can be conveniently carried out under microwave heating at a temperature of 130 ° C. for 15 to 25 hours.

Advantageously, the compounds of the present invention may be administered at a dosage of 0.001 to 1000 mg / 1 day, preferably 0.1 to 500 mg / 1 day.

When administered by inhalation route, the dosage of the compounds of the invention is advantageously in the range of 0.01 to 20 mg / 1 day, preferably 0.1 to 10 mg / 1 day.

Preferably, the compounds of the present invention are administered alone or in combination with other active ingredients for the prevention and / or treatment of obstructive respiratory diseases such as asthma, chronic bronchitis and chronic obstructive pulmonary disease (COPD).

However, the compounds of the present invention may be administered for the prevention and / or treatment of any disease involving the number, activity and migration of inflammatory cells.

Examples of such diseases include asthma and other allergic diseases, diseases involving inflammation, such as COPD, acute rhinitis; Reversible acute graft rejection and acute exacerbation of selected autoimmune diseases, graft-versus-host disease in bone marrow transplantation; Autoimmune diseases such as rheumatoid and other arthritis; Skin diseases such as systemic lupus erythematosus, systemic dermatitis, psoriasis; Acute exacerbation of inflammatory bowel disease, inflammatory eye disease, autoimmune blood disease and multiple sclerosis; Kidney, liver, heart and other organ transplants; Behcet's acute ocular syndrome, endogenous uveitis, atopic dermatitis, inflammatory bowel disease and nephrotic syndrome; Hodgkin's and non-Hodgkin's lymphoma, multiple myeloma and chronic lymphocytic leukemia (CLL); Thrombocytopenia associated with autoimmune hemolytic anemia and CLL; Leukemia and malignant lymphoma.

Preferably the compounds of the present invention can be administered for the prevention and / or treatment of asthma and COPD respiratory diseases such as mild or acute severe symptoms.

The invention is described in detail through the following examples.

In the reported experimental procedures, the following abbreviations can be used: TEA = triethylamine; DCM = dichloromethane; RT = room temperature; AcOEt = ethyl acetate; DMF = N, N-dimethylformamide; DMSO = dimethylsulfoxide; HATU = O- (7-Azabenzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium hexafluorophosphate; MeOH = methyl alcohol.

¹ H NMR spectra were recorded with a Bruker Avance II 300 Spectrometer Probehead 5 mm BBI 1H-BB (inverse probe head). Chemical shifts are expressed in ppm downfield from TMS as internal standard.

Mass spectra were recorded using Waters micromass ZQ under the following mass conditions: ESI POS 3.2 KV, Cone Voltage 25V, 350 ° C.

Liquid chromatography was performed with Waters UPLC Acquity with column Acquity UPLC BEH C18 1.7 μm 2.1 × 50 mm and UV detector: Waters Acquity 2996 PDA. Elution with two solvent systems: solvent A (H ₂ O-ACN 95: 5 + 0.1% TFA) and solvent B (H ₂ O-ACN 5:95 + 0.1% TFA), starting with solvent A 95% B up to 100% was performed for 7 minutes.

Optical rotation was measured using a Sodium-D line (equipped with Perkin Elmer polarimeter Mod 341).

Example  One

4- (4- Fluoro - Benzyloxy ) - Benzaldehyde Oxime  Preparation of (Intermediate 1)

To a mixture of 4- (4-fluoro-benzyloxy) -benzaldehyde and hydroxylamine hydrochloride (0.664 g, 9.56 mmol) in dry DCM (30 ml) at 0 ° C. under nitrogen atmosphere, TEA (1.332 ml, 9.56) mmol) was added and the reaction mixture was stirred at rt overnight. The mixture was purified directly by flash chromatography on silica gel with gradient elution from petroleum ether / AcOEt 85:15 to ether / AcOEt 70:30 to give the title compound 1 (2.03 g, 8.28 mmol, yield 95 %) Was generated.

LC-MS (ESI POS): 246.0 (MH +)

Starting from the appropriate aldehyde as starting material, the intermediates described in Table 4 were prepared using procedures similar to those described in Example 1.

[Table 4]

Example  2

N- [4- (4- Fluoro - Benzyloxy )-benzyl]- Hydroxylamine  Preparation of (Intermediate 2)

At 0 ° C., under nitrogen atmosphere, an aqueous 2.86 M (10%) HCl (17.64 ml, 50.4 mmol) solution was stirred in pure ethanol (25 ml), Compound 1 (1.237 g, 5.04 mmol) and boranepyridine complex (2.081). ml, 16.64 mmol) was added to the solution. After the addition was complete, the mixture was stirred at 0 ° C. for 10 minutes and at room temperature for 1 hour, basified to pH9 with solid sodium bicarbonate and sodium carbonate and then extracted with DCM (3 × 100 ml). The combined organic layers were dried (Na ₂ SO ₄ ) and evaporated in vacuo to yield Compound 2 (1.17 g, 4.73 mmol, 94% yield) as an off-white solid, which was used as such without further purification.

LC-MS (ESI POS): 215.0 (MH < + >)-NH ₂ OH

Using a procedure similar to that described in Example 2, the intermediates described in Table 5 below were obtained by reaction with the appropriate starting materials as indicated.

[Table 5]

Example  3

Acetic acid 2 - ((6S, 9R, 10S, 11S, 13S) -6,9- Difluoro -11- Hydroxy -10,13-dimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15- Decahydro -3H- Cyclopenta [a] phenanthrene Preparation of 17-yl) -2-oxo-ethyl ester (intermediate 4)

Under nitrogen atmosphere, butyric acid (9R, 10S, 11S, 13S, 17R) -17- (2-acetoxy-acetyl) -9-chloro-11-hydroxy-10,13-dimethyl- in anhydrous DMF (60 ml). 3-oxo-6,7,8,9, 10,11,12, 13, 14, 15, 16, 17-dodecahydro-3H-cyclopenta [a] phenanthrene-17-yl ester (intermediate 3) To a (2.48 g, 4.88 mmol) solution, potassium acetate (3.83 g, 39.0 mmol) was added and the reaction mixture was stirred at 100 ° C. for 1.5 h. The cooled reaction mixture was poured into ice and brine (200 ml) and the aqueous layer was extracted with AcOEt (3 × 150 ml). The combined organic extracts were washed with water and brine, dried over Na ₂ S0 ₄ and concentrated to afford crude title compound 4 (2.55 g) which was used in the next step without further purification.

¹ H NMR (300 MHz, DMSO- d ₆ ): ppm 7.29 (dd, 1 H), 6.99 (dd, 1 H), 6.29 (dd, 1 H), 5.98-6.15 (m, 1 H), 5.68 ( dddd, 1 H), 5.56 (dd, 1 H), 5.10 (d, 1 H), 4.92 (d, 1 H), 3.98-4.23 (m, 1 H), 2.56-2.83 (m, 1 H), 2.26-2.44 (m, 3H), 2.14-2.26 (m, 1H), 2.09 (s, 3H), 1.71-1.87 (m, 1H), 1.55-1.65 (m, 2H), 1.53 ( s, 3H), 1.15 (s, 3H).

LC-MS (ESI POS): 421.97 (MH +)

(6S, 9R, 10S, 11S, 13S) -6,9- Difluoro -11- Hydroxy -17- (2- Hydroxy -Acetyl) -10,13-dimethyl-6,7,8,9,10,11,12,13,14,15- Decahydro - Cyclopenta [a] pennants Preparation of Len-3-one (Intermediate 5)

To a solution of (Intermediate 4) (2.55 g, 6.06 mmol) in ethanol (100 ml), Candida Antarctica Lipase (2 U / mg) (510 mg, 6.06 mmol) was added and the reaction mixture was Stir overnight at 37 ° C. The reaction mixture was filtered, washed with methanol and the residue was purified by flash chromatography on silica gel (gradient elution: DCM / AcOEt 90: 10 to DCM / AcOEt 50:50), title compound 5 1.62 g (70.6% yield) was produced.

¹ H NMR (300 MHz, DMSO- d ₆ ): ppm 7.29 (dd, 1 H), 6.87 (dd, 1 H), 6.29 (dd, 1 H), 6.09-6.17 (m, 1 H), 5.67 ( dddd, 1 H), 5.53 (dd, 1 H), 4.77 (t, 1 H), 4.44 (dd, 1 H), 4.26 (dd, 1 H), 4.04-4.15 (m, 1 H), 2.56- 2.79 (m, 1 H), 2.39 (dd, 1 H), 2.25-2.35 (m, 2 H), 2.09-2.25 (m, 1 H), 1.76 (td, 1 H), 1.55-1.66 (m, 2H), 1.53 (s, 3H), 1.17 (s, 3H).

LC-MS (ESI POS): 379.99 (MH +)

Example  4

4- (4- ( Hydroxyamino ) Benzylthio ) Phenol (Intermediate 19) Preparation

Suspension of 4- (4-nitro-benzylsulfanyl) -phenol (647 mg, 2.476 mmol) and bismuth (iii) chloride (156 mg, 0.495 mmol) in EtOH (30 ml) and water (10 ml) under nitrogen atmosphere Cool to 0 ° C. Then potassium borohydride (134 mg, 2.476 mmol) was added in portions. The color of the suspension turned black, which was stirred at 0 ° C. for 2 hours. Further potassium borohydride (40.1 mg, 0.743 mmol) was added and the reaction mixture was stirred at 0 ° C. for 1 h. Diethyl ether was added and the mixture continued nitrogen bubbling and treated with HCl 0.5 N until pH was 7.

The mixture was partitioned between water and diethyl ether and the organic phase was dried over Na ₂ SO ₄ and filtered. The solvent was evaporated to afford intermediate 19 (597 mg, 2.414 mmol, 97% yield) as a light yellow solid. The crude residue was used as such in the next step.

LC-MS (ESI POS): 231.0 (MH < + >)-OH

Using a procedure similar to that described in Example 4, the intermediates described in Table 6 below were obtained from appropriate starting materials.

[Table 6]

Example  5

N- (biphenyl-4-yl) Hydroxylamine  Preparation of (Intermediate 24)

To a mixture of 4-nitrobiphenyl (400 mg, 2.008 mmol) and 5% rhodium (15 mg, 0.146 mmol) in carbon in tetrahydrofuran (15 ml), hydrazine hydrate (0.200 ml, 2.61 mmol) is added, Gas evaporation was observed. The reaction mixture was stirred for 25 minutes at room temperature, which was then partitioned between diethyl ether (90 ml) and brine (20 ml) and the phases separated. The aqueous phase was extracted with diethyl ether (90 ml) and the combined organic extracts were dried (Na ₂ SO ₄ ) and concentrated to give 370 mg of the desired compound (89% purity). This mixture was used as is in the next step.

LC-MS (ESI POS): 186.0 (MH +)

Using the procedure similar to that described in Example 5, the intermediates described in Table 7 were obtained by reacting the appropriate starting materials.

[Table 7]

Example  6

(4 aS ,4 bR , 5S, 6 aS , 6 bR , 9 aS , 10 aS , 10 bS , 12S) -4b, 12- Difluoro -8- [4- (4- Fluoro - Benzyloxy ) -Benzyl] -5- Hydroxy -6b- (2- Hydroxy -Acetyl) -4a, 6a-dimethyl-4a, 4b, 5,6,6a, 6b, 8,9,9a, 10,10a, 10b, 11,12-tetradecahydro-7-oxa-8- Keep it up - Pental Leno [ 2,1-a] phenanthrene Preparation of 2-one (Compound 6)

Intermediate 5 (600 mg, 1.586 mmol), crude N- (4- (4-fluorobenzyloxy) benzyl) hydroxylamine 2 (784 mg, 3.17 mmol) in paraethanol (30 ml) and paraformaldehyde (71.4 mg) , 2.378 mmol) was stirred at 105 ° C for 24 h. Subsequently, further paraformaldehyde (47.6 mg, 1.586 mmol) was added and the mixture was further stirred at 105 ° C. for 6 hours. The solvent was evaporated and the residue was purified by flash chromatography on silica gel (gradient elution: petroleum ether / AcOEt 9: 1 to petroleum ether / AcOEt 4: 6) to afford the title compound 6 (813 mg, 1.275 mmol, 80% yield. ) Was created.

¹ H NMR (300 MHz, DMSO- d ₆ ) ppm 7.42-7.56 (m, 2 H), 7.26 (dd, 1 H), 7.12-7.24 (m, 4 H), 6.93 (m, 2 H), 6.30 (dd, 1 H), 6.12 (s, 1 H), 5.49 -5.78 (m, 1 H), 5.43 (dd, 1 H), 5.05 (s, 2 H), 4.66 (br. s., 1 H ), 4.06-4.29 (m, 2H), 3.92 (dd, 1H), 3.81 (d, 1H), 3.73 (d, 1H), 3.31-3.54 (m, 2H), 2.56 -2.70 ( m, 1 H), 2.01-2.33 (m, 3 H), 1.87-1.97 (m, 1 H), 1.51-1.71 (m, 3 H), 1.49 (s, 3 H), 1.42 (dd, 1 H ), 0.80 (s, 3 H)

LC-MS (ESI POS): 638.24 MH +

[α] _D ²⁵ = + 146.7 (c 0.36; CHCl ₃ )

As indicated, by the cycloaddition reaction of intermediate 5 with appropriate hydroxylamine or hydroxylamine hydrochloride, the compounds described in Table 8 were prepared using procedures similar to those described above for compound 6 described in Example 6.

[Table 8]

Example  7

(4 aS ,4 bR , 5S, 6 aS , 6 bR , 9 aS , 10 aS , 10 bS , 12S) -4b, 12- Difluoro -8- [4- (4- Fluoro in- Benzyloxy ) -Benzyl] -5- Hydroxy -4a, 6a-dimethyl-2-oxo-2,4a, 4b, 5,6,6a, 8,9,9a, 10,10a, 10b, 11,12- Tetradecahydro -7-oxa-8- Keep it up - pen Taleno [2,1-a] phenanthrene-6b- Carboxylic acid  (Compound 7)

To a solution of 6 (60 mg, 1.035 mmol) in tetrahydrofuran (30 ml) and water (12 ml) at 0 ° C., bubbling air for 15 minutes, followed by 2 N sodium hydroxide (2.070 ml , 4. 14 mmol) was added slowly and the air was further bubbled at 0 ° C. for 5 more minutes. The reaction mixture was left at room temperature to reach room temperature, which was stirred for 24 hours at room temperature. The reaction mixture was acidified to pH 1 with 1N HCl and tetrahydrofuran was evaporated. The aqueous layer was extracted with AcOEt (100 ml x 3). The combined organic phases were washed with brine, dried (Na ₂ SO ₄ ) and concentrated. The crude product was triturated with petroleum ether to give 642 mg of the title compound 7 (99%).

LC-MS (ESI POS): 64.1 (MH +)

Using a procedure similar to that described in Example 7, the compounds described in Table 9 were obtained starting from the appropriate starting materials as indicated.

TABLE 9

Example  8

(4 aS ,4 bR , 5S, 6 aS , 6 bR , 9 aS , 10 aS , 10 bS , 12S) -8-((4- Fluoro - Benzyloxy ) -Benzyl) -4b, 12-di The Luo-5- Hydroxy -4a, 6a-dimethyl-2-oxo-2,4a, 4b, 5,6,6a, 8,9,9a, 10,10a, 10b, 11,12- Tetradecahydro -7-oxa-8- Keep it up - Pental Leno [ 2,1-a] phenanthrene -6b- Carbolic acid  S- Fluoromethyl  Preparation of Ester (Compound 8)

A mixture of compound 7 (620 mg, 0.994 mmol), HATU (378 mg, 0.994 mmol) and N-methylmorpholine (109 μl, 0.994 mmol) in anhydrous DMF (15 ml) was stirred at 70 ° C. under nitrogen atmosphere for 30 minutes. LC-MS showed that the desired activated ester was formed. This solution was cooled to room temperature and anhydrous sodium hydrogen sulfide (58.3 mg, 1.040 mmol) was added. The mixture was stirred at rt for 30 min, then 2M bromofluoromethane (746 μl, 1.491 mmol) solution in DMF was added and the mixture was stirred at rt overnight. Water (50 ml) was added to the reaction mixture and the formed precipitate was filtered off. The collected precipitate was purified by flash chromatography on silica gel using eluent acetone / petroleum ether 3: 7. After evaporation of the solvent, the residue was triturated with MeOH, filtered and dried in vacuo resulting in 280 mg of the title compound 8 (41.9% yield).

¹ H NMR (300 MHz, DMSO- d ₆ ) ppm 7.39-7.58 (m, 2H), 7.13-7.32 (m, 5H), 6.83-6.99 (m, 2H), 6.30 (dd, 1H) , 6.12 (s, 1 H), 5.87 (dd, 1 H), 5.76 (dd, 1 H), 5.51-5.75 (m, 1 H), 5.49 (dd, 1 H), 5.04 (s, 2 H) , 4.04-4.30 (m, 1 H), 3.89 (d, 1 H), 3.83 (d, 1 H), 3.3 1-3.51 (m, 2 H), 2.56-2.70 (m, 1 H), 2.02- 2.33 (m, 3 H), 1.83-1.95 (m, 1 H), 1.52-1.75 (m, 3 H), 1.49 (s, 3 H), 1.40-1.48 (m, 1 H), 0.88 (s, 3 H)

LC-MS (ESI POS): 672.19 (MH +)

[α] _D ²⁵ = + 122.9 (c 0.33; CHC1 ₃ )

Using a method analogous to that described in Example 8, starting from the appropriate starting material as indicated, the compounds shown in Table 10 were obtained.

[Table 10]

Example  9

4 aS ,4 bR , 5S, 6 aS , 6 bR , 9 aS , 10 aS , 10 bS , 12S) -4b, 12- Difluoro -5- Hydroxy -6b- (2- lower Idrock C-acetyl) -4a, 6a-dimethyl-8- [4- (4- Hydroxy - Phenylsulfanylmethyl ) - Phenyl 4a, 4b, 5,6,6a, 6b, 8,9,9a, 10,10a, 10b, 11,12-tetradecahydro-7-oxa-8- Keep it up -Pental Leno [2,1-a] phenanthrene Preparation of 2-one (Compound 37)

In a closed vessel, crude hydroxylamine 19 (597 mg, 2.414 mmol), compound 5 (457 mg, 1.207 mmol) and paraformaldehyde (109 mg, 3.62 mmol) were added to absolute ethanol (20 ml). It was suspended and it was heated at 105 ° C. under microwave irradiation for 1 hour 30 minutes. The reaction mixture was concentrated, diluted with 9 ml of MeOH and the mixture was directly purified directly by preparative HPLC (neutral phase) to yield the title compound (142 mg, 18.44% yield) as a pale yellow amorphous solid. It became.

¹ H NMR (300 MHz, DMSO- d ₆ ) ppm 9.49 (br. S., 1 H), 7.26 (dd, 1 H), 7.05 -7.20 (m, 4H), 6.79-6.94 (m, 2H ), 6.60-6.76 (m, 2H), 6.28 (dd, 1H), 6.08 (s, 1H), 5.52-5.77 (m, 1H), 5.51 (br.s., 1H), 4.91 (br. s., 1 H), 4.47 (d, 1 H), 4.26 (d, 1 H), 4.15-4.22 (m, 1 H), 4.08 (t, 1 H), 3.98 (s, 2 H ), 3.50-3.64 (m, 1 H), 2.54-2.71 (m, 2 H), 1.97-2.34 (m, 3 H), 1.51-1.83 (m, 4 H), 1.49 (s, 3 H), 0.90 (s, 3H).

LC-MS (ESI POS): 637.99 MH +

[α] _D ²⁵ = + 50.9 (c 0.31, MeOH)

Using a method analogous to that described in Example 9, starting from the appropriate starting material and intermediate 5 as indicated, the compounds described in Table 11 were obtained.

[Table 11]

Example  10

(4 aS ,4 bR , 5S, 6 aS , 6 bR , 9 aS , 10 aS , 10 bS , 12S) -4b, 12- Difluoro -5- Hydroxy -8- [4- (4-lower this Droxy- Phenylsulfanylmethyl ) - Phenyl ] -4a, 6a-dimethyl-2-oxo-2,4a, 4b, 5,6,6a, 8,9,9a, 10,10a, 10b, 11,12-tetradecahydro-7-oxa-8- Keep it up - Pental Leno [ 2, l-a] phenanthrene -6b- Carboxylic acid  Preparation of (Compound 49)

Compound 37 was dissolved in THF / water 3/1 mixture (28 mL). Sodium hydroxide (1.678 ml, 3.36 mmol) 2 M solution was added and the mixture was stirred for 24 h at room temperature in an open vessel. 1N HCl was added until pH was between 5 and 6 and the reaction mixture was partitioned between water and AcOEt. The organic phase was separated, dried over Na ₂ SO ₄ and concentrated to give 590 mg of desired compound 49 as a light yellow solid. The product obtained was used for next step without further purification.

LC-MS (ESI POS): 624.75 (MH +)

Example  11

(4 aS ,4 bR , 5S, 6 aS , 6 bR , 9 aS , 10 aS , 10 bS , 12S) -4b, 12- Difluoro -5- Hydroxy -4a, 6a-dimethyl-8- [4- (4- Hydroxy - Phenylsulfanylmethyl ) - Phenyl ] -2-oxo-2,4a, 4b, 5,6,6a, 8,9,9a, 10,10a, 10b, 11,12-tetradecahydro-7-oxa-8- Keep it up - Pental Leno [ 2,1-a] phenanthrene -6b- Carbolic acid  S- Fluoromethyl  Preparation of Ester (Compound 50)

A mixture of acid 49 (523 mg, 0.839 mmol), HATU (351 mg, 0.923 mmol) and 4-methylmorpholine (93 mg, 0.923 mmol) in anhydrous DMF (5 ml) was stirred for 1.5 hours at room temperature. Sodium hydrogen sulfide (188 mg, 3.36 mmol) was added and the mixture was stirred for 45 minutes at room temperature. Bromo fluoromethane (95 mg, 0.839 mmol) was then added and the solution was stirred at rt overnight. The mixture was partitioned between AcOEt and brine and the organic phase was dried over Na ₂ S0 ₄ and concentrated. The crude product was purified by preparative HPLC (neutral phase) to give compound 50 as a pale yellow solid (71 mg, 12.60% yield).

¹ H NMR (300 MHz, DMSO- d ₆ ) ppm 9.48 (s, 1 H), 7.24 (dd, 1 H), 7.10-7.20 (m, 4 H), 6.85-6.99 (m, 2H), 6.60 -6.74 (m, 2H), 6.28 (dd, 1H), 6.08 (s, 1H), 5.91 (dd, 1H), 5.83 (dd, 1H), 5.55 (dd, 1H), 5.43 -5.72 (m, 1 H), 4.16-4.28 (m, 1 H), 4.17 (t, 1 H), 3.99 (s, 2 H), 3.47-3.65 (m, 1 H), 2.56 -2.71 (m , 2 H), 2.05-2.26 (m, 2 H), 1.94-2.05 (m, 1 H), 1.54-1.91 (m, 4 H), 1.49 (s, 3 H), 0.97 (s, 3 H)

LC-MS (ESI POS): 672.21 (MH +)

[α] _D ²⁵ = + 51.8 (c 0.75, MeOH)

The pharmacological activity of the compounds of the present invention

In Vitro Research

Example  12

Glucocorticoid Receptor ( GR ) move ( translocation A) analysis protocol

Quantitative determination of GR nuclear migration of the compounds of the present invention can be performed according to ASSAY Drug Devel. Technology. This can be done via a novel cell-based GR-nuclear transfer assay in Complementation (EFC) format.

In the absence of glucocorticoids, the glucocorticoid receptors (GR) are complexed with various proteins, including heat shock proteins, located in the cytosol.

As glucocorticoids enter the cytoplasm through the cell membrane and bind to glucocorticoid receptors (GR), heat shock proteins are released and transported to the nucleus to regulate gene transcription.

The DiscoveRx analyzer uses EFC of beta-galactosidase (b-gal) as a marker of GR migration in engineered CHO-K1 biosensor cells. As designed using specific sequence additions and modifications, the b-gal enzyme receptor (EA) fragment is located in the nucleus. Small peptide enzyme donor (ED) fragments of b-gal were bound directly to the C terminus of GR and located in the cytoplasm in the absence of receptor signals. Upon binding to the GR ligand, the complex migrated to the nucleus, intact enzyme activity was restored by complementation, and b-gal activity was also detected.

CHO-K1 cells stably expressing the b-gal NLS-enzyme receptor fragment (EA) and the b-gal GR-enzyme donor (ED) fragment were 5 at 37 ° C. in F12 medium (Invitrogen, Carlsbad, CA). It is maintained under a humid atmosphere containing% CO ₂ and 95% air. This medium contains 10% FBS, 2 mM L-glutamine, 50 μg / ml streptomycin, 50 μg / ml streptomycin, and 250 μg / ml hygromycin and 500 μg / ml G418 (Invitrogen).

GR migration is measured using a kit containing a cell membrane permeation reagent and a beta-gal substrate (PathHunter Detection Kit; DiscoveRx, Fremont, CA). All compounds are screened using various concentrations ranging from 10 ⁻¹¹ to 10 ⁻⁶ M. This assay is performed in 48-wells (105 cells / well). Incubation of the screened compounds is performed at 37 ° C. for 2 hours. Detection is done by adding detection buffer from the kit supplied by DiscoveRx and stirring at room temperature for 1 hour. Luminescence is detected using a plate reader (CENTRO LB 960 microplate reader; Berthold Technologies).

Statistical analysis and determination of EC50 are performed using software (Prism-version 3.0 Graphpad Software (San Diego, Calif.)).

Some representative compounds of the present invention showed EC 50 <10 nM when tested using the analyzer described above.

Example  13

RAW  264.7 In macrophages LPS Inhibition of Induced Nitric Oxide Production

An in vitro model based on macrophage shock and cell line RAW 264.7 was used to test the anti-inflammatory effects of the corticosteroids of the present invention.

During the inflammatory process, large amounts of nitric oxide (NO) are produced by the inducible isoform of NO synthase (iNOS). Bacterial lipopolysaccharides (LPS) are commonly used in experimental environments to stimulate inflammatory responses in macrophages.

Cells are grown in phenol red free culture medium (RPM medium supplemented with heat-inactivated 10% calf serum, 2 mM glutamine, 100 U / ml penicillin and 0.1 mg / ml streptomycin). Cell stimulation begins by incubating the cells for 24 hours by adding LPS to a final concentration in the range of 100 ng / ml. Treatment with the compounds of the invention is carried out by adding these compounds in DMSO (0.1% final concentration) up to the desired final concentration up to 15 minutes before LPS exposure. As an index of nitric oxide production, the concentration of nitrite in the conditioned medium was measured by using a Greries colorimetric reaction (J. Neuroimmunol., 150, 29-36, 2004).

Statistical analysis and measurement of the IC50 is performed using software (Prism-version 3.0 Graphpad Software (San Diego, Calif.)).

Some representative compounds of the present invention exhibited an IC 50 <10 nM when examined by the analyzer described above.

Claims (15)

Compounds of formula (I) and pharmaceutically acceptable salts thereof.
[Formula (I)]

Wherein,
And _{(CH 2) n -Z- (CH} 2) n '-R 4, - - R 1 is
n is 0, 1 or 2;
n ' is 0, 1 or 2;
Z is a single bond or is selected from the group consisting of -S-, -O-, -C (O)-and -NR _3- ;
R ₃ is H, (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) haloalkyl, (C ₃ -C ₈ ) cycloalkyl, aryl, aryl (C ₁ -C ₆ ) alkyl and heteroaryl ( They are optionally substituted with -CN);
-R ₄ is
-H, halogen, -OH, -SH, -CN and -NR ₆ R ₇ ;
-Aryl (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkylsulfonyl, (C ₁ -C ₆ ) alkylcarbonyl, (C ₁ -C ₆ ) alkylcarboxyl, HO (C ₁ -C ₆ ) alkylcarboxyl, (C ₁ -C ₆ ) alkylamide and (C ₁ -C ₆ ) alkoxy, which are optionally substituted with oxo groups;
(C ₁ -C ₆ ) alkyl optionally substituted by one or more substituents selected from the group consisting of -halogen atom, -CN, -OH, -NH ₂ , -NO ₂ , -CF ₃ and -SH;
-(C ₂ -C ₆ ) alkynyl;
-(C ₅ -C ₁₇ ) alkenylcarbonyl; And
Mono-, non- or tricyclic saturated or partially saturated or unsaturated rings optionally substituted with one or more halogen atoms or oxo groups (eg (C ₃ -C ₈ ) cycloalkyl, aryl, (C ₅ -C ₁₀ Heterocycloalkyl or heteroaryl)
It is selected from the group consisting of;
R ₆ and R ₇ are independently selected from the group consisting of H, (C ₁ -C ₆ ) alkyl and (C ₁ -C ₆ ) alkoxy;
X and Y are independently H or a halogen atom;
R ₂ is-(CH ₂ ) _s -KA- (CH ₂ ) _t -W,-(CH ₂ ) _s -K- (CH ₂ ) _t -BW, and-(CH ₂ ) _S- (CHR ₅ ) -W is selected from the group consisting of;
s is 0 or 1;
t is 0 or 1;
-K is —CH═CH—groups, arylene groups and heteroarylene groups (such arylene and heteroarylene groups are halogen, (C ₁ -C ₆ ) alkyl, -OH, (C ₁ -C ₆ ) alkoxy and (C ₁ -C ₆ ) optionally substituted with one or more groups independently selected from haloalkyl);
A is selected from the group consisting of a bond, an -O- group and an -S- group;
B is selected from the group consisting of a single bond, an -O- group and an -S- group;
-W is aryl or heteroaryl, which aryl and heteroaryl groups are independently from halogen, -OH, (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy and (C ₁ -C ₆ ) haloalkyl Optionally substituted by one or more groups selected;
R ₅ is aryl or heteroaryl, which aryl and heteroaryl groups are independent from halogen, (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy, -OH and (C ₁ -C ₆ ) haloalkyl Optionally substituted by one or more groups selected from
However, in the compound of the formula (I), s is 1, K is optionally substituted heteroarylene, and t is 0, A or B is a single bond, provided that W is optionally substituted heteroaryl. The compound of claim 1, wherein the stereogenic carbon has stereochemistry as described in Formula (I ′).
Formula (I ')]

The compound of claim 1 or 2, wherein X and Y are fluorine atoms. 4. The compound of claim 1, wherein R ₁ is — (CH ₂ ) _n —Z— (CH ₂ ) _{n ′} —R ₄ , wherein n is 1, Z is a single bond, n ′ is 0, R ₄ is or an -OH group), R ₁ is _{- (CH 2) n -Z- (} CH 2) n '-R 4 Where n is 0, Z is -S-, n 'is 1 and R ₄ is a halogen atom, or R ₁ is-(CH ₂ ) _n -Z- (CH ₂ ) _n' -R ₄ ( Wherein n is 0, Z is a single bond, n 'is 1, and R ₄ is a halogen atom. The compound of claim 1, wherein R ₂ is — (CH ₂ ) _s -KA- (CH ₂ ) _t -W or-(CH ₂ ) _S -K- (CH ₂ ) _t- BW, wherein s is 0 or 1; K is optionally substituted arylene or heteroarylene; A is selected from the group consisting of a single bond, an -O- group and an -S- group; B is selected from the group consisting of a single bond, an -O- group and an -S- group; t is 0 or 1; W is optionally substituted aryl or heteroaryl. To claim 1 in any of the preceding of claim 5, wherein, R ₂ is _{- (CH 2) s -KA- (} CH 2) t -W or _{- (CH 2) S -K- (} CH 2) t - BW, wherein s is 1; K is optionally substituted arylene or heteroarylene; A is selected from the group consisting of a single bond, an -O- group and an -S- group; B is selected from the group consisting of a single bond, an -O- group and an -S- group; t is 0 or 1; W is optionally substituted aryl or heteroaryl. To claim 1 in any of the preceding of claim 5, wherein, R ₂ is _{- (CH 2) s -KA- (} CH 2) t -W or _{- (CH 2) S -K- (} CH 2) t - BW, wherein s is 0; K is optionally substituted arylene or heteroarylene; A is selected from the group consisting of a single bond, an -O- group and an -S- group; B is selected from the group consisting of a single bond, an -O- group and an -S- group; t is 0 or 1; W is optionally substituted aryl or heteroaryl. A compound according to any one of claims 1 to 5, which is a compound of the formula: or a pharmaceutically acceptable salt thereof.
(4aS, 4bR, 5S, 6aS, 6bR, 9aS, 10aS, 10bs, 12S) -4b, 12-difluoro-8- [4- (4-fluoro-benzyloxy) -benzyl] -5-hydroxy -6b- (2-hydroxy-acetyl) -4a, 6a-dimethyl-4a, 4b, 5,6,6a, 6b, 8,9,9a, 10,10a, 10b, 11,12-tetradecahydro- 7-oxa-8-aza-pentaleno [2,1-a] phenanthren-2-one;
(4aS, 4bR, 5S, 6aS, 6bR, 9aS, 10aS, 10bs, 12S) -4b, 12-difluoro-8- [4- (4-fluoro-benzyloxy) -benzyl] -5-hydroxy -4a, 6a-dimethyl-2-oxo-2,4a, 4b, 5,6,6a, 8,9,9a, 10,10a, 10b, 11,12-tetradecahydro-7-oxa-8-aza Pentaleno [2,1-a] phenanthrene-6b-carboxylic acid;
(4aS, 4bR, 5S, 6aS, 6bR, 9aS, 10aS, 10bs, 12S) -8-((4-fluoro-benzyloxy) -benzyl) -4b, 12-difluoro-5-hydroxy-4a , 6a-dimethyl-2-oxo-2,4a, 4b, 5,6,6a, 8,9,9a, 10,10a, 10b, 11,12-tetradecahydro-7-oxa-8-aza-pental Leno [2,1-a] phenanthrene-6b-carbothioic acid S-fluoromethyl ester;
(4aS, 4bR, 5S, 6aS, 6bR, 9aS, 10aS, 10bs, 12S) -8- (4-benzyloxy-benzyl) -4b, 12-difluoro-5-hydroxy-6b- (2-hydroxy Roxy-acetyl) -4a, 6a-dimethyl-4a, 4b, 5,6,6a, 6b, 8,9,9a, 10,10a, 10b, 11,12-tetradecahydro-7-oxa-8-aza Pentaleno [2,1-a] phenanthren-2-one;
(4aS, 4bR, 5S, 6aS, 6bR, 9aS, 10aS, 10bs, 12S) -8- (4-benzyloxy-benzyl) -4b, 12-difluoro-5-hydroxy-4a, 6a-dimethyl- 2-oxo-2,4a, 4b, 5,6,6a, 8,9,9a, 10,10a, 10b, 11,12-tetradecahydro-7-oxa-8-aza-pentaleno [2,1 -a] phenanthrene-6b-carboxylic acid;
(4aS, 4bR, 5S, 6bR, 9aS, 10aS, 10bs, 12S) -8-((S) -4-benzyloxy-benzyl) -4b, 12-difluoro-5-hydroxy-4a, 6a- Dimethyl-2-oxo-2,4a, 4b, 5,6,6a, 8,9,9a, 10,10a, 10b, 11,12-tetradecahydro-7-oxa-8-aza-pentaleno [2 , 1-a] phenanthrene-6b-carbothioic acid S-fluoromethyl ester;
(4aS, 4bR, 5S, 6aS, 6bR, 9aS, 10aS, 10bs, 12S) -4b, 12-difluoro-5-hydroxy-6b- (2-hydroxy-acetyl) -4a, 6a-dimethyl- 8- [4- (4-hydroxy-phenylsulfanylmethyl) -benzyl] -4a, 4b, 5,6,6a, 6b, 8,9,9a, 10,10a, 10b, 11,12-tetradeca Hydro-7-oxa-8-aza-pentaleno [2,1-a] phenanthren-2-one;
(4aS, 4bR, 5S, 6aS, 6bR, 9aS, 10aS, 10bs, 12S) -4b, 12-difluoro-5-hydroxy-6b- (2-hydroxy-acetyl) -4a, 6a-dimethyl- 8- [4- (4-hydroxy-phenylsulfanylmethyl) -phenyl] -4a, 4b, 5,6,6a, 6b, 8,9,9a, 10,10a, 10b, 11,12-tetradeca Hydro-7-oxa-8-aza-pentaleno [2,1-a] phenanthren-2-one;
(4aS, 4bR, 5S, 6aS, 6bR, 9aS, 10aS, 10bS, 12S) -4b, 12-difluoro-5-hydroxy-4a, 6a-dimethyl-8- [4- (4-hydroxy- Phenylsulfanylmethyl) -benzyl] -2-oxo-2,4a, 4b, 5,6,6a, 8,9,9a, 10,10a, 10b, 11,12- tetradecahydro-7-oxa-8 Aza-pentaleno [2, 1-a] phenanthrene-6b-carbothioic acid S-fluoromethyl ester;
(4aS, 4bR, 5S, 6aS, 6bR, 9aS, 10aS, 10bS, 12S) -4b, 12-difluoro-5-hydroxy-6b- (2-hydroxy-acetyl) -4a, 6a-dimethyl- 8- (5-methyl-2-thiophen-2-yl-oxazol-4-ylmethyl) -4a, 4b, 5,6,6a, 6b, 8,9,9a, 10,10a, 10b, 11 , 12-tetradecahydro-7-oxa-8-aza-pentaleno [2,1-a] phenanthren-2-one;
(4aS, 4bR, 5S, 6aS, 6bR, 9aS, 10aS, 10bs, 12S) -4b, 12-difluoro-5-hydroxy-4a, 6a-dimethyl-8- [4- (4-hydroxy- Phenylsulfanylmethyl) -phenyl] -2-oxo-2,4a, 4b, 5,6,6a, 8,9,9a, 10,10a, 10b, 11,12- tetradecahydro-7-oxa-8 Aza-pentaleno [2, 1-a] phenanthrene-6b-carbothioic acid S-fluoromethyl ester;
(4aS, 4bR, 5S, 6aS, 6bR, 9aS, 10aS, 10bs, 12S) -4b, 12-difluoro-5-hydroxy-6b- (2-hydroxy-acetyl) -4a, 6a-dimethyl- 8- (4-thiophen-2-yl-phenyl) -4a, 4b, 5,6,6a, 6b, 8,9,9a, 10,10a, 10b, 11,12-tetradecahydro-7-oxa -8-aza-pentaleno [2,1-a] phenanthren-2-one;
(4aS, 4bR, 5S, 6aS, 6bR, 9aS, 10aS, 10bs, 12S) -8-biphenyl-4-yl-4b, 12-difluoro-5-hydroxy-6b- (2-hydroxy- Acetyl) -4a, 6a-dimethyl-4a, 4b, 5,6,6a, 6b, 8,9,9a, 10,10a, 10b, 11,12-tetradecahydro-7-oxa-8-aza-pental Reno [2,1-a] phenanthren-2-one;
(4aS, 4bR, 5S, 6aS, 6bR, 9aS, 10aS, 10bs, 12S) -4b, 12-difluoro-5-hydroxy-6b- (2-hydroxy-acetyl) -4a, 6a-dimethyl- 8- (4-methoxyphenylsulfanylmethyl) -4a, 4b, 5,6,6a, 6b, 8,9,9a, 10,10a, 10b, 11,12-tetradecahydro-7-oxa-8 Aza-pentaleno [2,1-a] phenanthren-2-one;
(4aS, 4bR, 5S, 6aS, 6bR, 9aS, 10aS, 10bS, 12S) -8- (4-benzyl-phenyl) -4b, 12-difluoro-5-hydroxy-6b- (2-hydroxy -Acetyl) -4a, 6a-dimethyl-4a, 4b, 5,6,6a, 6b, 8,9,9a, 10,10a, 10b, 11,12-tetradecahydro-7-oxa-8-aza- Pentaleno [2,1-a] phenanthren-2-one;
(4aS, 4bR, 5S, 6aS, 6bR, 9aS, 10aS, 10bs, 12S) -4b, 12-difluoro-5-hydroxy-6b- (2-hydroxy-acetyl) -4a, 6a-dimethyl- 8- (4-pyridin-4-ylmethyl-phenyl) -4a, 4b, 5,6,6a, 6b, 8,9,9a, 10,10a, 10b, 11,12-tetradecahydro-7-oxa -8-aza-pentaleno [2,1-a] phenanthren-2-one;
(4aS, 4bR, 5S, 6aS, 6bR, 9aS, 10aS, 10bs, 12S) -4b, 12-difluoro-8- [4- (4-fluoro-benzylsulfanyl) -phenyl] -5-hydr Hydroxy-6b- (2-hydroxy-acetyl) -4a, 6a-dimethyl-4a, 4b, 5,6,6a, 6b, 8,9,9a, 10,10a, 10b, 11,12-tetradecahydro -7-oxa-8-aza-pentaleno [2,1-a] phenanthren-2-one;
(4aS, 4bR, 5S, 6aS, 6bR, 9aS, 10aS, 10bs, 12S) -8- [4- (4-chloro-phenoxymethyl) -phenyl] -4b, 12-difluoro-5-hydroxy -6b- (2-hydroxy-acetyl) -4a, 6a-dimethyl-4a, 4b, 5,6,6a, 6b, 8,9,9a, 10,10a, 10b, 11,12-tetradecahydro- 7-oxa-8-aza-pentaleno [2,1-a] phenanthren-2-one;
(4aS, 4bR, 5S, 6aS, 6bR, 9aS, 10aS, 10bs, 12S) -4b, 12-difluoro-5-hydroxy-6b- (2-hydroxy-acetyl) -8- [4- ( 4-methoxy-phenoxymethyl) -phenyl] -4a, 6a-dimethyl-4a, 4b, 5,6,6a, 6b, 8,9,9a, 10,10a, 10b, 11,12-tetradecahydro -7-oxa-8-aza-pentaleno [2,1-a] phenanthren-2-one;
(4aS, 4bR, 5S, 6aS, 6bR, 9aS, 10aS, 10bs, 12S) -8-biphenyl-3-yl-4b, 12-difluoro-5-hydroxy-6b- (2-hydroxy- Acetyl) -4a, 6a-dimethyl-4a, 4b, 5,6,6a, 6b, 8,9,9a, 10,10a, 10b, 11,12-tetradecahydro-7-oxa-8-aza-pental Reno [2,1-a] phenanthren-2-one;
(4aS, 4bR, 5S, 6aS, 6bR, 9aS, 10aS, 10bs, 12S) -8- [4- (3-chloro-phenoxymethyl) -phenyl] -4b, 12-difluoro-5-hydroxy -6b- (2-hydroxy-acetyl) -4a, 6a-dimethyl-4a, 4b, 5,6,6a, 6b, 8,9,9a, 10,10a, 10b, 11,12-tetradecahydro- 7-oxa-8-aza-pentaleno [2,1-a] phenanthren-2-one;
(4aS, 4bR, 5S, 6aS, 6bR, 9aS, 10aS, 10bs, 12S) -4b, 12-difluoro-5-hydroxy-6b- (2-hydroxy-acetyl) -4a, 6a-dimethyl- 8- (3-p-tolyloxymethyl-phenyl) -4a, 4b, 5,6,6a, 6b, 8,9,9a, 10,10a, 10b, 11,12-tetradecahydro-7-oxa- 8-aza-pentaleno [2,1-a] phenanthren-2-one;
(4aS, 4bR, 5S, 6aS, 6bR, 9aS, 10aS, 10bs, 12S) -8- [4- (3-chloro-benzylsulfanyl) -phenyl] -4b, 12-difluoro-5-hydroxy -6b- (2-hydroxy-acetyl) -4a, 6a-dimethyl-4a, 4b, 5,6,6a, 6b, 8,9,9a, 10,10a, 10b, 11,12-tetradecahydro- 7-oxa-8-aza-pentaleno [2,1-a] phenanthren-2-one;
(4aS, 4bR, 5S, 6aS, 6bR, 9aS, 10aS, 10bS, 12S) -4b, 12-difluoro- Phenyl] -4a, 6a-dimethyl-2-oxo-2,4a, 4b, 5,6,6a, 8,9,9a, 10,10a, 10b, 11,12-tetradecahydro- -Aza-pentaleno [2, 1-a] phenanthrene-6b-carboxylic acid;
(4aS, 4bR, 5S, 6aS, 6bR, 9aS, 10aS, 10bS, 12S) -4b, 12-difluoro- Benzyl] -4a, 6a-dimethyl-2-oxo-2,4a, 4b, 5,6,6a, 8,9,9a, 10,10a, 10b, 11,12-tetradecahydro-7-oxa-8 Aza-pentaleno [2, 1-a] phenanthrene-6b-carboxylic acid. A pharmaceutical composition comprising a compound according to any one of claims 1 to 8 and at least one pharmaceutically acceptable carrier and / or excipient. A compound according to any one of claims 1 to 8, a beta2-agonist, an antimuscarinic agent, a corticosteroid, a mitogen-activated protein kinase (P38 MAP kinase) inhibitor, a nuclear factor kappa-B kinase At least one active ingredient selected from the group consisting of subunit beta (IKK2) inhibitors, human neutrophil elastase (HNE) inhibitors, phosphodiesterase 4 (PDE4) inhibitors, leukotriene modulators, nonsteroidal anti-inflammatory agents (NSAIDs) and mucus modulators Compound compounded. The compound according to any one of claims 1 to 8 for use as a medicament. The compound according to any one of claims 1 to 8 for the prevention and / or treatment of respiratory diseases characterized by airway obstruction. The compound according to any one of claims 1 to 8 for the treatment and / or prevention of respiratory diseases, namely asthma or COPD, characterized by airway obstruction according to claim 12. Use of a compound according to any one of claims 1 to 8 for the manufacture of a medicament for the prevention and / or treatment of respiratory diseases characterized by airway obstruction. A method for the prophylaxis and / or treatment of respiratory diseases characterized by airway obstruction, comprising administering to a patient in need thereof a therapeutically effective amount of a compound according to any one of claims 1 to 8.